Comprehensive analysis of microRNA expression in lumbar facet joint capsules and synovium of patients with osteoarthritis: Comparison between early-stage and late-stage osteoarthritis samples from a single individual.

BACKGROUND: MicroRNA is attracting attention as a therapeutic target for osteoarthritis. We focused on joint capsules and synovium in lumbar facet joint osteoarthritis. The purpose of this study was to identify microRNAs that are upregulated in lumbar facet joint capsules and synovium with osteoarthritis. METHODS: We included patients who underwent spinal fusion for degenerative lumbar spine diseases. We selected patients who had both early-stage and late-stage facet joint osteoarthritis in a single individual. We extracted joint capsule and synovium samples from these patients and isolated microRNAs. During the screening phase, we compared early-stage and late-stage osteoarthritis samples from the same individual. We identified microRNAs with >2-fold change in expression in 75% or more of patients with late-stage osteoarthritis using next generation sequencing. During the technical validation phase, the same samples were used for real-time polymerase chain reaction. We identified microRNAs with >2-fold change in expression in 62.5% or more of patients with late-stage osteoarthritis. RESULTS: Of 40 patients who underwent spinal fusion, we selected eight patients with both early-stage and late-stage facet joint osteoarthritis. During the screening phase, we identified eight upregulated microRNAs out of 2274 microRNAs in late-stage OA. In late-stage OA, two microRNAs (miR-133a-5p and miR-144-3p) were upregulated in seven patients and six microRNAs (miR-133a-3p, miR-133b, miR-206, miR-20a-5p, miR-301a-3p, and miR-32-5p) were upregulated in six patients. During the technical validation phase, we found significant upregulation of miR-144-3p expression in late-stage osteoarthritis compared with early-stage osteoarthritis. Expression of the other microRNAs was not significantly different according to the paired-t test. However, miR-133a-3p, miR-133b, and miR-206 were upregulated >2-fold in 62.5% or more of patients with late-stage osteoarthritis. CONCLUSIONS: Some of the microRNAs identified in this study might be involved in joint capsule degeneration or synovitis.

Relationship between Facial Color Changes and Psychological Problems Associated with Lower Back Pain.

Background and Objectives: The aim of this study was to determine whether a non-contact sensor that detects complexion changes can be used to assess the psychological state of patients with chronic lower back pain (LBP). Materials and Methods: Twenty-six patients with LBP (LBP group; mean age = 68.0 ± 13.9 years) and 18 control subjects without LBP (control group; mean age = 60.8 ± 16.1 years) were included in the study. All the subjects in the two groups wore headphones when asked LBP-related and LBP-unrelated questions. During questioning, the facial image of the subjects was captured using a video camera, and the complexion of the subjects was converted into red, green, and blue (RGB) values. RGB correlation coefficients (RGBCCs; range: 0-1) represent the difference in complexion between LBP-related and LBP-unrelated questions. A high RGBCC indicates that the brain is more activated by LBP-related questions than by LBP-unrelated questions. We also noted the scores of subjects on the Numerical Rating Scale (NRS), Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ), Pain Catastrophizing Scale (PCS), and Hospital Anxiety and Depression Scale (HADS). Results: There were no significant differences in RGBCC between the control and LBP groups (0.64 versus 0.56, p = 0.08). In the LBP group, no correlation was observed between RGBCC and each examination item of NRS, JOABPEQ, and HADS. In contrast, a correlation was observed between RGBCC and the rumination subscale of PCS in the LBP group (Spearman's rank correlation coefficient = 0.40, p = 0.04). Conclusions: The complexion of patients with catastrophic thinking changes when the patients are asked LBP-related questions.

Evaluation of infections in orthopedic patients using next-generation sequencing.

INTRODUCTION: Culture tests are used to diagnose infections, but there are various problems such as low sensitivity in detecting infections in orthopedic cases. To address this problem, next generation sequencing (NGS) analysis, which can comprehensively search for bacterial genes, is being applied clinically. In this study, we examined whether NGS analysis was useful in evaluating infections in orthopedic cases. METHODS: The participants were 23 patients suspected of having an infection between 2016 and 2017. Samples were collected from tissues suspected of being infected and were subjected to culture tests and NGS analysis, and the positive rates from the culture tests and from the NGS analysis were compared. We also attempted to determine cutoff value for the NGS analysis. RESULTS: A total of 20 cases were ultimately diagnosed as infections and 3 cases were diagnosed as non-infections. The sensitivity of the culture tests was 70%, and the sensitivity of the NGS analysis was 55%. When the NGS analysis was performed with the diversity index set to the cut-off value, the sensitivity was 75% for the Simpson index. In this study, the sensitivity was 90% when the analysis was performed using the NGS index, which is a combination of the diversity index and the OTUs (operational taxonomic units) value. CONCLUSION: NGS analysis using the NGS index showed excellent sensitivity and specificity compared to culture tests. NGS analysis is therefore a useful modality for assessing infections in orthopedic cases.

Neuroinvasiveness of the MR766 strain of Zika virus in IFNAR-/- mice maps to prM residues conserved amongst African genotype viruses.

Zika virus (ZIKV) strains are classified into the African and Asian genotypes. The higher virulence of the African MR766 strain, which has been used extensively in ZIKV research, in adult IFNα/ß receptor knockout (IFNAR-/-) mice is widely viewed as an artifact associated with mouse adaptation due to at least 146 passages in wild-type suckling mouse brains. To gain insights into the molecular determinants of MR766's virulence, a series of genes from MR766 were swapped with those from the Asian genotype PRVABC59 isolate, which is less virulent in IFNAR-/- mice. MR766 causes 100% lethal infection in IFNAR-/- mice, but when the prM gene of MR766 was replaced with that of PRVABC59, the chimera MR/PR(prM) showed 0% lethal infection. The reduced virulence was associated with reduced neuroinvasiveness, with MR766 brain titers ≈3 logs higher than those of MR/PR(prM) after subcutaneous infection, but was not significantly different in brain titers of MR766 and MR/PR(prM) after intracranial inoculation. MR/PR(prM) also showed reduced transcytosis when compared with MR766 in vitro. The high neuroinvasiveness of MR766 in IFNAR-/- mice could be linked to the 10 amino acids that differ between the prM proteins of MR766 and PRVABC59, with 5 of these changes affecting positive charge and hydrophobicity on the exposed surface of the prM protein. These 10 amino acids are highly conserved amongst African ZIKV isolates, irrespective of suckling mouse passage, arguing that the high virulence of MR766 in adult IFNAR-/- mice is not the result of mouse adaptation.

Bilateral facet effusion is a risk factor for segmental instability with cervical injury without vertebral fracture.

Magnetic resonance imaging (MRI) is effective in identifying cervical spine injury after trauma. However, cervical instability without major bone injury or dislocation is challenging to assess. Hence, the current study aimed to investigate and compare the MRI and radiography findings of segmental instability in patients with cervical spine injury. We investigated 34 participants with cervical spine injury without vertebral fracture. Based on the radiography findings, the participants were categorized into two: group A with segmental instability (n = 11) and group B without segmental instability (n = 23). Both groups were compared in terms of the presence of segmental instability on radiography and MRI. Anterior longitudinal ligament (ALL) injury, disc injury, and bilateral facet effusion were observed in 6/11, 5/11, and 7/11 patients in group A and in 5/23, 2/23 and 7/23 patients in group B, respectively. The results showed significant differences (p < 0.05). Moreover, 2 and 10 of 11 patients in group A and 16 and 7 of 23 patients in group B presented with hemi lateral facet effusion and paravertebral muscle injury, respectively. However, the results did not significantly differ. According to a logistic regression analysis, bilateral facet effusion after trauma was associated with cervical segmental instability (odd ratio: 10.6, 95% confidence interval: 1.31-84.7). Facet joint effusion might be caused by capsule injury during trauma. Most participants with segmental instability had ALL, disc, and flavum injury and bilateral facet effusion. Therefore, we need to consider bilateral facet effusion with other soft tissue damage of the cervical spine as an association factor to show the instability.

Fast-Growing Cervical Juxtafacet Cyst Mimicking Epidural Hematoma: A Case Report.

CASE: A 75-year-old man, who was a carpenter, experienced neck pain and numbness in the upper and lower extremities while hammering a nail and later developed a gait disturbance. Initial magnetic resonance imaging (MRI) revealed a tumor-like mass at the C5 epidural space compressing the spinal cord. The first diagnosis was cervical epidural hematoma. The following day, the patient's symptom deteriorated. A second MRI revealed an increase in the size of the mass, and surgery was performed. Operative findings included a juxtafacet cyst. CONCLUSION: Repeated job-related load on the facet joint in this patient caused rapid progression of facet cysts, causing myelopathy similar to an epidural hematoma.

A Surrogate Animal Model for Screening of Ebola and Marburg Glycoprotein-Targeting Drugs Using Pseudotyped Vesicular Stomatitis Viruses.

Filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fever in humans and nonhuman primates with high mortality rates. There is no approved therapy against these deadly viruses. Antiviral drug development has been hampered by the requirement of a biosafety level (BSL)-4 facility to handle infectious EBOV and MARV because of their high pathogenicity to humans. In this study, we aimed to establish a surrogate animal model that can be used for anti-EBOV and -MARV drug screening under BSL-2 conditions by focusing on the replication-competent recombinant vesicular stomatitis virus (rVSV) pseudotyped with the envelope glycoprotein (GP) of EBOV (rVSV/EBOV) and MARV (rVSV/MARV), which has been investigated as vaccine candidates and thus widely used in BSL-2 laboratories. We first inoculated mice, rats, and hamsters intraperitoneally with rVSV/EBOV and found that only hamsters showed disease signs and succumbed within 4 days post-infection. Infection with rVSV/MARV also caused lethal infection in hamsters. Both rVSV/EBOV and rVSV/MARV were detected at high titers in multiple organs including the liver, spleen, kidney, and lungs of infected hamsters, indicating acute and systemic infection resulting in fatal outcomes. Therapeutic effects of passive immunization with an anti-EBOV neutralizing antibody were specifically observed in rVSV/EBOV-infected hamsters. Thus, this animal model is expected to be a useful tool to facilitate in vivo screening of anti-filovirus drugs targeting the GP molecule.

Post-column detection of cadmium chelators by high-performance liquid chromatography using 5,10,15,20-tetraphenyl-21H,23H-porphinetetrasulfonic acid.

Cd(II) is toxic to many species, including humans, because it inactivates a number of enzymes and induces cytopathic effects in the liver, kidney, and skeletal tissues in humans. Metallothionein and glutathione (GSH) play a major role in the protection against Cd(II)-induced toxicity in mammalian cells. In this study, a relatively simple method for detecting trace amounts of Cd(II) chelators was developed by using 5,10,15,20-tetraphenyl-21H,23H-porphinetetrasulfonic acid (TPPS). The TPPS-Cd(II) complex was added to the elutions of high-performance liquid chromatography. The Cd(II) chelators separated by column chromatography were mixed with Cd(II)-bound TPPS (TPPS-Cd(II)). Cd(II) from TPPS-Cd(II) was chelated by the eluted Cd(II) chelators, resulting in the formation of free TPPS. The absorbance of TPPS shifted from 434 nm (TPPS-Cd(II)) to 414 nm (TPPS), and this characteristic shift was used to estimate the quantity and affinity of the Cd(II) chelators. This new method was compared with the bathocuproine disulfonate (BCS) method developed in our previous study. Instead of BCS-Cu(I), TPPS-Cd(II) was used as the colorimetric reagent. The experimental setup of the TPPS-based method is more general, and the preparation of the colorimetric solution is also much simpler than the BCS method. To verify the efficacy of this new method, we determined the actual Cd(II)-chelating ability of GSH in horse blood; the obtained concentration was in good agreement with the previously reported value.

Brain Activation in a Cynomolgus Macaque Model of Chymopapain-Induced Discogenic Low Back Pain: A Preliminary Study.

INTRODUCTION: There is currently a lack of translatable, preclinical models of low back pain (LBP). Chymopapain, a proteolytic enzyme used to treat lumbar intervertebral disc (IVD) herniation, could induce discogenic LBP. The current study developed a behavioral model of discogenic LBP in nonhuman primates. Significant brain activation is observed in clinical LBP. Thus, the current study also sought to define brain activation over time in a macaque with discogenic LBP. METHODS: Responses to pressure applied to the back at L4/L5 were measured in eight adult male Macaca fasciculata using a pressure algometer. The nucleus pulpous of the IVD between L4 and L5 was aspirated and chymopapain (1 mg/mL) was injected under fluoroscopic guidance (n = 2). In two macaques, the nucleus pulpous was only aspirated. Brain activation in response to pressure applied to the lower back was assessed using a 3.0T magnetic resonance imaging scanner in four macaques before and 1, 3, 9, and 14 days after treatment. RESULTS: The mean (±SD) response pressure before treatment was 1.4 ± 0.1 kg. One day after chymopapain treatment, the response pressure decreased to 0.6 ± 0.05 kg (P < 0.01), suggestive of pressure hypersensitivity. Over time, the pressure thresholds following chymopapain treatment gradually returned to normal. Following aspiration only, the response pressure was 1.4 ± 0.05 kg, which was not significantly different from the uninjured controls. There was activation of the secondary somatosensory cortex and insular cortex one and three days after chymopapain treatment; there was no activation following aspiration only. CONCLUSIONS: Enzymatic treatment of the nucleus pulpous leads to acute LBP and pressure-evoked activation in pain-related brain areas. The current model of discogenic LBP parallels clinical LBP and could be used to further elaborate the mechanism of acute LBP.

Improving biosynthesis of AuPd core-shell nanoparticles through Escherichia coli with the assistance of phytochelatin for catalytic enhanced chemiluminescence and benzyl alcohol oxidation.

In this work, AuPd core-shell nanoparticles (NPs) biosynthesized through Arabidopsis thaliana phytochelatin synthase-modified Escherichia coli (Au-Pd/AtPCS1-E. coli) with catalytic enhanced chemiluminescence (CL) and benzyl alcohol oxidation (BAO) was investigated. Such biosynthesis of AuPd core-shell NPs was obviously enhanced due to insertion of the gene sequence of Arabidopsis thaliana phytochelatin synthase (AtPCS1) to a plasmid vector (pET-28b) of Escherichia coli (E. coli). The obtained Arabidopsis thaliana phytochelatin synthase-modified Escherichia coli (AtPCS1-E. coli) could generate phytochelatins (PCs, (γ-Glu-Cys)n-Gly, n > 1) for efficient capture and enrichment of Au3+. The component and morphology of AuPd core-shell NPs were checked through X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM) and energy dispersive spectrometer (EDS). Catalytic CL (in H2O2-luminol system) and BAO (in H2O2-benzyl alcohol system) effect with different experimental conditions were examined, respectively. These results revealed that multifunctional PCs could effectively facilitate biosynthetic process of AuPd core-shell NPs with better distribution, higher yield and lower cost while stronger CL intensity and higher conversion could be obtained for further quantitative analysis and application.

Determinants of Zika virus host tropism uncovered by deep mutational scanning.

Arboviruses cycle between, and replicate in, both invertebrate and vertebrate hosts, which for Zika virus (ZIKV) involves Aedes mosquitoes and primates1. The viral determinants required for replication in such obligate hosts are under strong purifying selection during natural virus evolution, making it challenging to resolve which determinants are optimal for viral fitness in each host. Herein we describe a deep mutational scanning (DMS) strategy2-5 whereby a viral cDNA library was constructed containing all codon substitutions in the C-terminal 204 amino acids of ZIKV envelope protein (E). The cDNA library was transfected into C6/36 (Aedes) and Vero (primate) cells, with subsequent deep sequencing and computational analyses of recovered viruses showing that substitutions K316Q and S461G, or Q350L and T397S, conferred substantial replicative advantages in mosquito and primate cells, respectively. A 316Q/461G virus was constructed and shown to be replication-defective in mammalian cells due to severely compromised virus particle formation and secretion. The 316Q/461G virus was also highly attenuated in human brain organoids, and illustrated utility as a vaccine in mice. This approach can thus imitate evolutionary selection in a matter of days and identify amino acids key to the regulation of virus replication in specific host environments.

Distinguishing analgesic drugs from non-analgesic drugs based on brain activation in macaques with oxaliplatin-induced neuropathic pain.

The antineoplastic agent oxaliplatin is a first-line treatment for colorectal cancer. However, neuropathic pain, characterized by hypersensitivity to cold, emerges soon after treatment. In severe instances, dose reduction or curtailing treatment may be necessary. While a number of potential treatments for oxaliplatin-induced neuropathic pain have been proposed based on preclinical findings, few have demonstrated efficacy in randomized, placebo-controlled clinical studies. This failure could be related, in part, to the use of rodents as the primary preclinical species, as there are a number of distinctions in pain-related mechanisms between rodents and humans. Also, an indicator of preclinical pharmacological efficacy less subjective than behavioral endpoints that is translatable to clinical usage is lacking. Three days after oxaliplatin treatment in Macaca fascicularis, a significantly reduced response latency to cold (10 °C) water was observed, indicating cold hypersensitivity. Cold-evoked bilateral activation of the secondary somatosensory (SII) and insular (Ins) cortex was observed with functional magnetic resonance imaging. Duloxetine alleviated cold hypersensitivity and significantly attenuated activation in both SII and Ins. By contrast, neither clinically used analgesics pregabalin nor tramadol affected cold hypersensitivity and cold-evoked activation of SII and Ins. The current findings suggest that suppressing SII and Ins activation leads to antinociception, and, therefore, could be used as a non-behavioral indicator of analgesic efficacy in patients with oxaliplatin-induced neuropathic pain.

Pain-related behavior and brain activation in cynomolgus macaques with naturally occurring endometriosis.

STUDY QUESTION: Can pain be objectively assessed in macaques with naturally occurring endometriosis? SUMMARY ANSWER: Behavioral, pharmacological and in vivo brain imaging findings indicate that pain can be quantified in macaques with endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is characterized by abdominopelvic hypersensitity. The mechanism by which endometriosis evokes pain is largely unknown, as currently available analgesics offer limited pain relief. Thus, there is a need for both greater understanding of the in vivo mechanism of endometriosis-associated pain and better methods of testing novel therapeutics. STUDY DESIGN, SIZE, DURATION: Pain-related behavior and brain activation were assessed in five cynomolgus macaques with endometriosis. Three healthy female macaques served as controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Abdominopelvic sensitivity to force was assessed with an algometer. Activation of brain areas using block design force stimulation and the effects of a single dose of the analgesic drug morphine and 2-month treatment with the progestin dienogest on brain activation were observed via functional magnetic resonance imaging. MAIN RESULTS AND THE ROLE OF CHANCE: Pain response thresholds in macaques with endometriosis were significantly less than that of healthy macaques (P = 0.0003). In addition, non-noxious force activated the insula and thalamus, which was reduced with morphine and 2-month dienogest treatment. LIMITATIONS, REASONS FOR CAUTION: The specific role of cysts, such as peritoneal cysts, in endometriosis pain was not explored. While non-noxious stimulation activated the insula and thalamus, macaques were sedated during fMRI scans. Current findings need further confirmation in a larger cohort. WIDER IMPLICATIONS OF THE FINDINGS: The current study demonstrated central sensitization and related pain behavior in macaques with naturally occurring endometriosis. Altered functioning of the central nervous system could be the focus of future mechanistic studies and for the development of novel therapeutics. STUDY FUNDING/COMPETING INTEREST(S): Supported by a grant from the Shizuoka Industrial Foundation. All authors are employees of Hamamatsu Pharma Research, Inc.

Enhanced biosynthesis of CdS nanoparticles through Arabidopsis thaliana phytochelatin synthase-modified Escherichia coli with fluorescence effect in detection of pyrogallol and gallic acid.

In this work, CdS nanoparticles (CdS NPs) biosynthesized through Arabidopsis thaliana phytochelatin synthase-modified Escherichia coli (CdS/AtPCS1-E. coli) with fluorescence (FL) performance for detection of pyrogallol and gallic acid was investigated. Through expression of the AtPCS1 gene inside E. coli cells by pET28b vector, biosynthesis of CdS NPs was greatly enhanced due to generation of phytochelatins (PCs, (γ-Glu-Cys)n-Gly, n ≥ 2) for efficient capture of Cd2+. The expression of AtPCS1 and concentration of glutathione (GSH) and PCs were detected by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and high performance liquid chromatography (HPLC), respectively. The morphology and component were checked through scanning electron microscope (SEM), transmission electron microscopy (TEM) and energy dispersive spectrometer (EDS). FL effect with different experimental conditions were examined. In addition, it is also applied to determination of pyrogallol and gallic acid. These results revealed that multifunctional PCs could effectively facilitate biosynthesis of CdS NPs with higher yield, better distribution and lower cost while stronger FL intensity could be obtained for quantitative analysis.

[Pharmacological profile of a novel nonhuman primate model of knee osteoarthritis].

A number of promising compounds developed in rodent arthritis models lack efficacy in clinical osteoarthritis (OA) pain. To enhance successful translation of preclinical findings, a nonhuman primate (NHP) model of knee OA was developed and characterized using behavioral assessments designed for use in the NHP. A unilateral medial meniscectomy (MMx) was performed and animals underwent an exercise regimen. Decreased ipsilateral knee pressure threshold, pressure "hyperalgesia", and decreased ipsilateral weight bearing, suggestive of pain at rest were observed. The sensitivity of the pain-related behaviors to pharmacological manipulation was evaluated. A single dose of the opioid morphine reduced pain-related behaviors. Likewise, the serotonin-norepinephrine reuptake inhibitor duloxetine reduced pain-related behavior, and efficacy was similar to that of morphine. By contrast, the anticonvulsant pregabalin did not significantly affect pain-related behavior. Repeated dosing with the non-steroidal anti-inflammatory drug (NSAID) diclofenac reduced pain-related behaviors whereas repeated dosing with the NK1 receptor antagonist aprepitant did not. The drug effects observed in the NHP OA model mirror the efficacy observed clinically.

Gaps in Understanding Mechanism and Lack of Treatments: Potential Use of a Nonhuman Primate Model of Oxaliplatin-Induced Neuropathic Pain.

The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.

Elimination of eosinophils using anti-IL-5 receptor alpha antibodies effectively suppresses IL-33-mediated pulmonary arterial hypertrophy.

Interleukin (IL)-5 is a critical regulator of eosinophils and a therapeutic target for asthma. The administration of anti-IL-5 or anti-IL-5 receptor (IL-5R) antibodies has been shown to reduce eosinophil counts and ameliorate asthmatic symptoms in studies on animal models of allergy as well as in human clinical trials. In order to explore other potential clinical uses of IL-5R antibodies, we used an animal model of IL-33-mediated pulmonary arterial hypertrophy. We first generated chimeric monoclonal antibodies against the mouse IL-5 receptor α chain (IL-5Rα), which comprised an Fc region from human IgG1 and a Fab region from a previously established anti-mouse IL-5Rα monoclonal antibody. To investigate the role of antibody-dependent cell-mediated cytotoxicity (ADCC), chimeric antibodies that lacked ADCC were prepared. These antibodies recognized IL-5Rα to the same extent as the ADCC-sufficient antibodies. Administration of chimeric antibodies with ADCC resulted in the elimination of eosinophils from the lung and thus suppressed the development of arterial hypertrophy. This effect was attenuated in mice treated with antibodies lacking ADCC. Taken together, the results of this study provided a potential use for anti-IL-5Rα antibodies in the treatment of arterial hypertrophy, which leads to pulmonary hypertension.

Brain activity changes in a macaque model of oxaliplatin-induced neuropathic cold hypersensitivity.

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.

Antinociceptive effect of clinical analgesics in a nonhuman primate model of knee osteoarthritis.

A number of potential analgesic pharmacotherapies developed in preclinical osteoarthritis animal models have failed clinical trials. A possible basis for the lack of translation of preclinical findings to clinical efficacy is the use of a preclinical species that is distinct from that of humans. The current study tested clinical analgesics in a nonhuman primate model of knee osteoarthritis. Following a medial meniscectomy, the animals developed a robust ipsilateral reduction in knee pressure threshold (hyperalgesia) and an ipsilateral reduction in weight bearing (resting pain). The serotonin-noradrenalin reuptake inhibitor duloxetine and opioid morphine increased ipsilateral pressure threshold and weight bearing. By contrast, the anticonvulsant pregabalin did not affect either pressure hyperalgesia or resting pain. The current findings in the nonhuman primate model of osteoarthritis parallel clinical findings, in that duloxetine and opioids are used in the management of osteoarthritis pain whereas pregabalin is not. The current findings also suggest the possible differentiation of pharmacotherapeutics in a nonhuman primate model, of distinguishing potential clinically useful analgesics for the management of osteoarthritic pain from those that are not.

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin-induced neuropathic cold hypersensitivity.

Oxaliplatin is a first-line treatment for colorectal cancer. However, shortly following treatment, cold-evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin-induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy-induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water ("cold hypersensitivity") was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin-induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin-treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin-induced peripheral neuropathy.