An updated HACOR score for predicting the failure of noninvasive ventilation: a multicenter prospective observational study.

BACKGROUND: Heart rate, acidosis, consciousness, oxygenation, and respiratory rate (HACOR) have been used to predict noninvasive ventilation (NIV) failure. However, the HACOR score fails to consider baseline data. Here, we aimed to update the HACOR score to take into account baseline data and test its predictive power for NIV failure primarily after 1-2 h of NIV. METHODS: A multicenter prospective observational study was performed in 18 hospitals in China and Turkey. Patients who received NIV because of hypoxemic respiratory failure were enrolled. In Chongqing, China, 1451 patients were enrolled in the training cohort. Outside of Chongqing, another 728 patients were enrolled in the external validation cohort. RESULTS: Before NIV, the presence of pneumonia, cardiogenic pulmonary edema, pulmonary ARDS, immunosuppression, or septic shock and the SOFA score were strongly associated with NIV failure. These six variables as baseline data were added to the original HACOR score. The AUCs for predicting NIV failure were 0.85 (95% CI 0.84-0.87) and 0.78 (0.75-0.81) tested with the updated HACOR score assessed after 1-2 h of NIV in the training and validation cohorts, respectively. A higher AUC was observed when it was tested with the updated HACOR score compared to the original HACOR score in the training cohort (0.85 vs. 0.80, 0.86 vs. 0.81, and 0.85 vs. 0.82 after 1-2, 12, and 24 h of NIV, respectively; all p values < 0.01). Similar results were found in the validation cohort (0.78 vs. 0.71, 0.79 vs. 0.74, and 0.81 vs. 0.76, respectively; all p values < 0.01). When 7, 10.5, and 14 points of the updated HACOR score were used as cutoff values, the probability of NIV failure was 25%, 50%, and 75%, respectively. Among patients with updated HACOR scores of ≤ 7, 7.5-10.5, 11-14, and > 14 after 1-2 h of NIV, the rate of NIV failure was 12.4%, 38.2%, 67.1%, and 83.7%, respectively. CONCLUSIONS: The updated HACOR score has high predictive power for NIV failure in patients with hypoxemic respiratory failure. It can be used to help in decision-making when NIV is used.

Use of high-flow nasal cannula and noninvasive ventilation in patients with COVID-19: A multicenter observational study.

BACKGROUND: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) in patients with COVID-19 is debated. METHODS: This study was performed in four hospitals of China from January to March 2020. We retrospectively enrolled 23 and 13 COVID-19 patients who used HFNC and NIV as first-line therapy, respectively. RESULTS: Among the 23 patients who used HFNC as first-line therapy, 10 experienced HFNC failure and used NIV as rescue therapy. Among the 13 patients who used NIV as first-line therapy, one (8%) used HFNC as rescue therapy due to NIV intolerance. The duration of HFNC + NIV (median 7.1, IQR: 3.5-12.2 vs. 7.3, IQR: 5.3-10.0 days), intubation rate (17% vs. 15%) and mortality (4% vs. 8%) did not differ between patients who used HFNC and NIV as first-line therapy. In total cohorts, 6 (17%) patients received intubation. Time from initiation of HFNC or NIV to intubation was 8.4 days (IQR: 4.4-18.5). And the time from initiation of HFNC or NIV to termination in patients without intubation was 7.1 days (IQR: 3.9-10.3). Among all the patients, C-reactive protein was independently associated with intubation (OR = 1.04, 95% CI: 1.01-1.07). In addition, no medical staff got nosocomial infection who participated in HFNC and NIV management. CONCLUSIONS: In critically ill patients with COVID-19 who used HFNC and NIV as first-line therapy, the duration of HFNC + NIV, intubation rate and mortality did not differ between two groups. And no medical staff got nosocomial infection during this study.

A Waveform Image Method for Discriminating Micro-Seismic Events and Blasts in Underground Mines.

The discrimination of micro-seismic events (events) and blasts is significant for monitoring and analyzing micro-seismicity in underground mines. To eliminate the negative effects of conventional discrimination methods, a waveform image discriminant method was proposed. Principal component analysis (PCA) was applied to extract the raw features of events and blasts through their waveform images that established by the recorded field data, and transform them into the new uncorrelated features. The amount of initial information retained in the derived features could be determined quantitatively by the contribution rate. The binary classification models were established by utilizing the support vector machine (SVM) algorithm and the PCA derived waveform image features. Results of four groups of cross validation show that the optimal values for the accuracy of events and blasts, total accuracy, and quality evaluation parameter MCC are 97.1%, 93.8%, 93.60%, and 0.8723, respectively. Moreover, the computation efficiency per accuracy (CEA) was introduced to quantitatively evaluate the effects of contribution rate on classification accuracy and computation efficiency. The optimal contribution rate was determined to be 0.90. The waveform image discriminant method can automatically classify events and blasts in underground mines, ensuring the efficient establishment of high-quality micro-seismic databases and providing adequate data for the subsequent seismicity analysis.

Temporal changes of fine root overyielding and foraging strategies in planted monoculture and mixed forests.

BACKGROUND: Mixed forests are believed to enhance ecosystem functioning and sustainability due to complementary resource use, environmental benefits and improved soil properties. The facilitation between different species may induce overyielding. Meanwhile, the species-specific fine root foraging strategies and tradeoffs would determine the structure and dynamics of plant communities. Here the aim was to investigate the admixing effects of fine-root biomass, vertical distribution and morphology in Pinus massoniana-Cinnamomum camphora mixed plantations and corresponding monocultures at 10-, 24- and 45-year old stands. RESULTS: The fine root biomass in the Pinus-Cinnamomum mixed forest exerted a certain degree of overyielding effect. These positive admixing effects, however, did not enhance with forest stand development. The overall relative yield total ranged from 1.83 and 1.51 to 1.33 in 10-, 24- and 45-year-old stand, respectively. The overyielding was mainly attributed to the over-performance of late successional species, Cinnamomum, in mixed stands. The vertical fine root biomass distribution model showed fine roots of pioneer species, Pinus, shifted to the superficial layer when mixed with Cinnamomum. Furthermore, the specific root length (SRL) of Pinus was significantly higher in Pinus-Cinnamomum mixed stands than that in monocultures, and the magnitude of differences increased over time. However, the vertical fine-root distribution and SRL for Cinnamomum did not show significant differences between monoculture and mixtures. CONCLUSIONS: Our results indicated that the magnitude of fine root overyielding in mixed forests showed a high degree of consistency with the total amount of fine root biomass itself, suggesting the overyielding effects in mixed forests were correlated with the degree of belowground interaction and competition degree involved. The late successional species, Cinnamomum, invested more carbon to belowground by increasing the fine root biomass in mixtures. While the pioneer species, Pinus, adapted to the presence of the species Cinnamomum by modification of vertical distribution and root morphological plasticity in the mixtures. These species-specific fine root foraging strategies might imply the differences of forest growth strategies of co-occurring species and contribute to the success and failure of particular species during the succession over time.

Involvement of Spinal CCR5/PKCγ Signaling Pathway in the Maintenance of Cancer-Induced Bone Pain.

Cancer-induced bone pain (CIBP) is a challenging medical problem that considerably influences cancer patients' quality of life. Currently, few treatments have been developed to conquer CIBP because of a poor understanding of the potential mechanisms. Our previous work has proved that spinal RANTES (a major ligand for CCR5) was involved in the maintenance of CIBP. In this study, we attempted to investigate whether spinal CCR5 and its downstream PKCγ pathway is involved in the maintenance of CIBP. Inoculation of Walker 256 cells into the tibia could induce a marked mechanical allodynia with concomitant upregulation of spinal CCR5 and p-PKCγ expression from day 6 to day 15 after inoculation. Spinal CCR5 was prominently expressed in microglia, and mechanical allodynia was attenuated by intrathecal injection of DAPTA (a specific antagonist of CCR5) with downregulation of spinal CCR5 and p-PKCγ expression levels at day 15 in inoculated rats. Pre-intrathecal injection of RANTES could reverse the anti-allodynia effects of DAPTA. Intrathecal administration of GF109203X (an inhibitor of PKC) could alleviate mechanical allodynia as well as decrease of spinal p-PKCγ expression level, but no influence on spinal CCR5 level. Our findings suggest that CCR5/PKCγ signaling pathway in microglia may contribute to the maintenance of CIBP in rats.

Spinal SET7/9 may contribute to the maintenance of cancer-induced bone pain in mice.

Cancer-induced bone pain (CIBP) profoundly influences patients' quality of life. Exploring the mechanisms by which CIBP occurs is essential for developing efficacious therapies. Various studies have shown that proinflammatory factors were involved in CIBP. SET domain containing lysine methyltransferase 7/9 (SET7/9) may modulate the expression of NF-κB-dependent proinflammatory genes in vitro. However, whether SET7/9 may participate in the maintenance of CIBP remains unknown. In this study, NCTC 2472 cells were inoculated into the intramedullary space of the femur to establish a mouse model of CIBP. Upregulation of spinal SET7/9 expression was related to pain behaviours in tumour-inoculated mice. Intrathecal cyproheptadine (10 or 20 nmol) attenuated response to painful stimuli in a dose-dependent manner. Moreover, there was a concomitant decrease in spinal SET7/9 and RANTES expression. The antinociceptive effects of cyproheptadine were abolished by pre-intrathecal administration of SET 7/9 (0.2 µg) for 30 minutes before intrathecal cyproheptadine (20 nmol) administration. These results indicated that spinal SET7/9 may contribute to the maintenance of CIBP in mice. Hence, targeting of spinal SET7/9 might be a useful alternative therapy for the treatment of CIBP.

Connexin 43 Mediates CXCL12 Production from Spinal Dorsal Horn to Maintain Bone Cancer Pain in Rats.

Tumor metastasis to bone can subsequently lead to bone cancer pain (BCP). Currently, BCP is difficult to conquer due to a poor understanding of the potential mechanisms. Several studies have indicated that astrocyte-specific connexin 43 (Cx43) was involved in the neuropathic pain, and Cx43 induced the release of chemokine CXCL12 in bone marrow stromal cells. However, whether spinal Cx43 mediates the production of CXCL12 to participate in the maintenance of BCP is still unknown. Here we showed that Walker 256 tumor cells inoculation into the tibia induced a significant mechanical allodynia, which was accompanied by upregulation of spinal p-Cx43 and CXCL12 expression levels from day 6 to day 18 after inoculation. Spinal Cx43 was mainly expressed in astrocytes, and intrathecal (43)Gap26 (a selective Cx43 blocker) markedly attenuated mechanical allodynia as well as reduced p-Cx43 and CXCL12 expression at day 18 after inoculation. Pre-intrathecal administration of CXCL12 almost abolished the attenuated mechanical allodynia by (43)Gap26. Furthermore, intrathecal injection of anti-CXCL12 neutralizing antibody could ameliorate mechanical allodynia with concomitant inhibition of upregulation of CXCL12 expression, but not influence on p-Cx43 expression. Our results indicate that Cx43 mediates CXCL12 production from spinal dorsal horn in astrocytes to maintain bone cancer pain in rats. These findings may improve our understanding of the underlying mechanisms of BCP and provide a novel target for the treatment of BCP.

Prediction of noninvasive ventilation failure using the ROX index in patients with de novo acute respiratory failure.

BACKGROUND: The ratio of SpO2/FiO2 to respiratory rate (ROX) index is commonly used to predict the failure of high-flow nasal cannula. However, its predictive power for noninvasive ventilation (NIV) failure is unclear. METHODS: This was a secondary analysis of a multicenter prospective observational study, intended to update risk scoring. Patients with de novo acute respiratory failure were enrolled, but hypercapnic patients were excluded. The ROX index was calculated before treatment and after 1-2, 12, and 24 h NIV. Differences in predictive power for NIV failure using the ROX index, PaO2/FiO2, and PaO2/FiO2/respiratory rate were tested. RESULTS: A total of 1286 patients with de novo acute respiratory failure were enrolled. Of these, 568 (44%) experienced NIV failure. Patients with NIV failure had a lower ROX index than those with NIV success. The rates of NIV failure were 92.3%, 70.5%, 55.3%, 41.1%, 35.1%, and 29.5% in patients with ROX index values calculated before NIV of ≤ 2, 2-4, 4-6, 6-8, 8-10, and > 10, respectively. Similar results were found when the ROX index was assessed after 1-2, 12, and 24 h NIV. The area under the receiver operating characteristics curve was 0.64 (95% CI 0.61-0.67) when the ROX index was used to predict NIV failure before NIV. It increased to 0.71 (95% CI 0.68-0.74), 0.74 (0.71-0.77), and 0.77 (0.74-0.80) after 1-2, 12, and 24 h NIV, respectively. The predictive power for NIV failure was similar for the ROX index and for the PaO2/FiO2. Likewise, no difference was found between the ROX index and the PaO2/FiO2/respiratory rate, except at the time point of 1-2 h NIV. CONCLUSIONS: The ROX index has moderate predictive power for NIV failure in patients with de novo acute respiratory failure.

Early assessment of the efficacy of noninvasive ventilation tested by HACOR score to avoid delayed intubation in patients with moderate to severe ARDS.

BACKGROUND: Use of noninvasive ventilation (NIV) in patients with moderate to severe ARDS is controversial. We aimed to use HACOR (combination of heart rate, acidosis, consciousness, oxygenation and respiratory rate) score to comprehensively assess the efficacy of NIV in ARDS patients with PaO2/FiO2 ⩽ 150 mmHg. METHODS: Secondary analysis was performed using the data collected from two databases. We screened the ARDS patients who used NIV as a first-line therapy. Patients with PaO2/FiO2 ⩽ 150 mmHg were enrolled. NIV failure was defined as requirement of intubation. RESULTS: A total of 224 moderate to severe ARDS patients who used NIV as a first-line therapy were enrolled. Of them, 125 patients (56%) experienced NIV failure and received intubation. Among the intubated patients, the survivor had shorter time from initiation of NIV to intubation than nonsurvivors (median 10 vs 22 h, p < 0.01). The median differences of HACOR score before and 1-2 h of NIV were 1 point (interquartile range: 0-3). We defined the patients with △HACOR >1 as responders (n = 102) and the rest to non-responders (n = 122). Compared to non-responders, the responders had higher HACOR score before NIV. However, the HACOR score was lower in the responders than non-responders after 1-2 h, 12 h, and 24 h of NIV. The responders also had lower NIV failure rate (36% vs 72%, p < 0.01) and lower 28-day mortality (32% vs 47%, p = 0.04) than non-responders. CONCLUSIONS: NIV failure was high among patients with moderate to severe ARDS. Delayed intubation is associated with increased mortality. The reduction of HACOR score after 1-2 h of NIV can identify the patients who respond well to NIV.

Association between ARDS Etiology and Risk of Noninvasive Ventilation Failure.

Rationale: The etiology of acute respiratory distress syndrome (ARDS) may play an important role in the failure of noninvasive ventilation (NIV). Objectives: To explore the association between ARDS etiology and risk of NIV failure. Methods: A multicenter prospective observational study was performed in 17 intensive care units in China from September 2017 to December 2019. Patients with ARDS who used NIV as a first-line therapy were enrolled. The etiology of ARDS was recorded at study entry. Results: A total of 306 patients were enrolled. Of the patients, 146 were classified as having pulmonary ARDS (ARDSp) and 160 were classified as having extrapulmonary ARDS (ARDSexp). From initiation to 24 hours of NIV, the respiratory rate, heart rate, arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2), and arterial carbon dioxide pressure improved slower in patients with ARDSp than those with ARDSexp. Patients with ARDSp experienced more NIV failure (55% vs. 28%; P < 0.01) and higher 28-day mortality (47% vs. 14%; P < 0.01). The adjusted odds ratios of NIV failure and 28-day mortality were 5.47 (95% confidence interval [CI], 3.04-9.86) and 10.13 (95% CI, 5.01-20.46), respectively. In addition, we combined the presence of ARDSp, presence of septic shock, age, nonpulmonary sequential organ failure assessment score, respiratory rate at 1-2 hours of NIV, and PaO2/FiO2 at 1-2 h of NIV to develop a risk score of NIV failure. With the increase of the risk score, the rate of NIV failure increased. The area under the curve of the receiver operating characteristic was 0.84 (95% CI, 0.79-0.89) and 0.81 (0.69-0.92) in the training and validation cohorts, respectively. Using 5.5 as cutoff value to predict NIV failure, the sensitivity and specificity was good. Conclusions: Among patients with ARDS who used NIV as a first-line therapy, ARDSp was associated with slower improvement, more NIV failure, and higher 28-day mortality than ARDSexp. The risk score combined presence of ARDSp, presence of septic shock, age, nonpulmonary sequential organ failure assessment score, respiratory rate at 1-2 hours of NIV, and PaO2/FiO2 at 1-2 hours of NIV has high accuracy to predict NIV failure among ARDS population.

Predictors of the Failure of Noninvasive Ventilation in Patients With Acute Respiratory Failure Caused by Severe Acute Pancreatitis: A Prospective Observational Study.

OBJECTIVE: The aim of the study was to identify risk factors associated with the failure of noninvasive ventilation (NIV) in patients with severe acute pancreatitis (SAP). METHODS: Patients who received NIV as a first-line therapy because of acute respiratory failure caused by SAP were enrolled. RESULTS: A total of 133 patients were enrolled. Of the patients, 32 (24%) experienced NIV failure. Male sex (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.48-12.22), older age (OR, 1.04; 95% CI, 1.01-1.08), a higher Acute Physiology and Chronic Health Evaluation II score (OR, 1.18; 95% CI, 1.03-1.36), and a procalcitonin level greater than 3.8 ng/mL (OR, 6.28; 95% CI, 2.04-19.31) were independently associated with NIV failure. The receiver operating characteristic curves for predicting NIV failure were 0.67, 0.72, and 0.76 tested by age, procalcitonin, and Acute Physiology and Chronic Health Evaluation II score, respectively. From initiation to 24 hours, the patients in the NIV failure group had a higher proportion of Glasgow Coma Scale scores of 14 or less, a higher proportion of pH ≤7.35, and higher respiratory rates than ones in the successful NIV group. CONCLUSIONS: One of 4 SAP patients experience NIV failure. Age, sex, disease severity, level of inflammation, and vital signs can be used to predict NIV failure.

The experience of high-flow nasal cannula in hospitalized patients with 2019 novel coronavirus-infected pneumonia in two hospitals of Chongqing, China.

BACKGROUND: The outbreak of a novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) is currently ongoing in China. Most of the critically ill patients received high-flow nasal cannula (HFNC) oxygen therapy. However, the experience of HFNC in this population is lacking. METHODS: We retrospectively screened 318 confirmed patients with NCIP in two hospitals of Chongqing, China, from January 1st to March 4th, 2020. Among them, 27 (8.4%) patients experienced severe acute respiratory failure including 17 patients (63%) treated with HFNC as first-line therapy, 9 patients (33%) treated with noninvasive ventilation (NIV) and one patient (4%) treated with invasive ventilation. HFNC failure was defined by the need of NIV or intubation as rescue therapy. RESULTS: Of the 17 HFNC patients, 7 (41%) experienced HFNC failure. The HFNC failure rate was 0% (0/6) in patients with PaO2/FiO2 > 200 mm Hg vs. 63% (7/11) in those with PaO2/FiO2 ≤ 200 mm Hg (p = 0.04). Compared with baseline data, the respiratory rate significantly decreased after 1-2 h of HFNC in successful group [median 26 (IQR: 25-29) vs. 23 (22-25), p = 0.03]. However, it did not in the unsuccessful group. After initiation of NIV as rescue therapy among the 7 patients with HFNC failure, PaO2/FiO2 significantly improved after 1-2 h of NIV [median 172 (150-208) mmHg vs. 114 (IQR: 79-130) under HFNC, p = 0.04]. However, two out of seven (29%) patients with NIV as rescue therapy ultimately received intubation. Among the 27 patients with severe acute respiratory failure, four patients were eventually intubated (15%). CONCLUSIONS: Our study indicated that HFNC was the most common ventilation support for patients with NCIP. Patients with lower PaO2/FiO2 were more likely to experience HFNC failure.

The utilization of aerosol therapy in mechanical ventilation patients: a prospective multicenter observational cohort study and a review of the current evidence.

BACKGROUND: Aerosol delivery via mechanical ventilation has been reported to vary significantly among different intensive care units (ICU). The optimal technique for using each aerosol generator may need to be updated with the available evidence. METHODS: A 2-week prospective multicenter observational cohort study was implemented to record aerosol delivery for mechanically ventilated adult patients in Chinese ICUs. Our data included the type of aerosol device and its placement, ventilator type, humidification, and aerosolized medication administered. A guide for the optimal technique for aerosol delivery during mechanical ventilation was summarized after a thorough literature review. RESULTS: A total of 160 patients (105 males) from 28 ICUs were enrolled, of whom 125 (78.1%) received aerosol therapy via invasive ventilation. Among these 125 patients, 53 received ventilator-integrated jet nebulizer, with 64% (34/53) of them placed the nebulizer close to Y piece in the inspiratory limb. Further, 56 patients used continuous nebulizers, with 84% (47/56) of them placed the nebulizer close to the Y piece in the inspiratory limb. Of the 35 patients who received aerosol therapy via noninvasive ventilation, 30 received single limb ventilators and continuous nebulizers, with 70% (21/30) of them placed between the mask and exhalation port. Only 36% (58/160) of the patients received aerosol treatments consistent with optimal practice. CONCLUSIONS: Aerosol delivery via mechanical ventilation varied between ICUs, and only 36% of the patients received aerosol treatments consistent with optimal practice. ICU clinicians should be educated on the best practices for aerosol therapy, and quality improvement projects aim to improve the quality and outcome of patients with the optimal technique for aerosol delivery during mechanical ventilation are warranted.

Noninvasive ventilation failure in patients with hypoxemic respiratory failure: the role of sepsis and septic shock.

BACKGROUND: Sepsis and septic shock are common in noninvasive ventilation (NIV) patients. However, studies on the association between sepsis and NIV failure are lacking. METHODS: A prospective multi-center observational study was performed in 16 Chinese intensive care units (ICUs). Patients who used NIV due to hypoxemic respiratory failure were enrolled. Sepsis and septic shock were diagnosed according to the guideline of sepsis-3. RESULTS: A total of 519 patients were enrolled. Sepsis developed in 365 patients (70%) and septic shock developed in 79 patients (15%). However, 75 patients (14%) had no sepsis. NIV failure was 23%, 38%, and 61% in patients, with no sepsis, sepsis, and septic shock, respectively. Multivariate analysis found that sepsis [odds ratio (OR) = 1.95, 95% confidence interval (CI): 1.06-3.61] and septic shock (OR = 2.47, 95% CI: 1.12-5.45) were independently associated with NIV failure. In sepsis and septic shock population, the NIV failure was 13%, 31%, 37%, 53%, and 67% in patients with sequential organ failure assessment (SOFA) scores of ⩽2, 3-4, 5-6, 7-8, and ⩾9, respectively. Patients with nonpulmonary induced sepsis had similar NIV failure rate compared with those with pulmonary induced sepsis, but had higher proportion of septic shock (37% versus 10%, p ⩽ 0.01) and lower ICU mortality (10% versus 22%, p ⩽ 0.01). CONCLUSIONS: Sepsis was associated with NIV failure in patients with hypoxemic respiratory failure, and the association was stronger in septic shock patients. NIV failure increased with the increase of organ dysfunction caused by sepsis. The reviews of this paper are available via the supplemental material section.

Correlation between Ki-67 Expression and Hemodynamics of Contrast-Enhanced Ultrasound in Patients with Breast Infiltrative Ductal Carcinoma.

Breast cancer causes great threats to public health worldwide. The aim of this study was to investigate the correlation between Ki-67 expression and the hemodynamics of contrast-enhanced ultrasound (CEUS) in patients with infiltrative ductal carcinoma (IDC). CEUS was performed on 109 masses in 85 IDC cases before resection. Based on the immunohistochemical staining on the antigen Ki-67, the masses were divided into negative group, weakly positive group, positive group, and strong-positive group. Significant statistical differences were noticed in time to peak, arrive intensity, and peak intensity in the positive groups compared with the negative group. Compared with the positive groups, the negative group showed significant statistical differences in arrive intensity and peak intensity. The antigen Ki-67 was positively correlated with arrived intensity, intensity changes, and rising curve's slope. In contrast, it was negatively correlated with arrived time, time to peak, and continuous time. The hemodynamic parameters of CEUS were correlated with the expression of antigen Ki-67. On this basis, Ki-67 is an effective supplement to the diagnosis of IDC.

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer-Induced Bone Pain.

Cancer-induced bone pain (CIBP) is seriously disruptive to the quality of life in cancer patients, and present therapies are limited. The Bv8/prokineticin 2, a new family of chemokines, has been demonstrated to be involved in inflammatory and neuropathic pain. However, whether it is involved in CIBP remains unclear. This study was designed to examine whether spinal Bv8 was involved in the development of CIBP in rats. A rat CIBP model was constructed by injecting Walker 256 carcinoma cells into the medullary cavity of rat tibia. Tibia inoculation with Walker 256 tumour cells resulted in the development of mechanical hyperalgesia. Compared with sham rats, spinal Bv8 mRNA and protein levels were markedly and time-dependently increased in CIBP rats. Intrathecal administration of Bv8 neutralizing antibody (5 ng) could markedly attenuate pain behaviour as well as up-regulation of spinal TNF-α expression at day 18 after inoculation. Intrathecal pre-treatment with synthetic Bv8 (50 pg) almost completely abolished these effects. These data suggested that spinal Bv8/prokineticin 2 participated in the development of CIBP. Targeting of spinal Bv8 might be a promising strategy for the management of cancer-induced bone pain.

Evidence for involvement of spinal RANTES in the antinociceptive effects of triptolide, a diterpene triepoxide, in a rat model of bone cancer pain.

It has been shown that triptolide has beneficial effects in the treatment of neuropathic pain, but its effects on bone cancer pain (BCP) remain unclear. In this study, we aimed to explore the potential role of spinal regulated activation of normal T cell expressed and secreted (RANTES) in the antinociceptive effects of triptolide on BCP. A BCP model was induced by injecting Walker 256 mammary gland carcinoma cells into the intramedullary space of rat tibia. Intrathecal administration of triptolide (0.5, 1, 2 µg) could dose-dependently alleviate mechanical hyperalgesia and spontaneous pain. In addition, there were also concomitant decreases in RANTES mRNA and protein expression levels in spinal dorsal horn. These results suggest that the antinociceptive effects of triptolide are related with inhibition of spinal RANTES expression in BCP rats. The findings of this study may provide a promising drug for the treatment of BCP.

Involvement of spinal CC chemokine ligand 5 in the development of bone cancer pain in rats.

In this study, we aimed to investigate the role of spinal CC chemokine ligand 5 (CCL5) in the development of bone cancer pain (BCP). A BCP model was established by inoculation of Walker 256 cells into the intramedullary space of rat tibia. The levels of spinal CCL5 mRNA and protein expression significantly and time dependently increased in BCP rats compared with sham rats. On day 15 after inoculation, intrathecal administration of anti-CCL5 neutralizing antibody (4 µg) significantly attenuated the established mechanical hyperalgesia in the Walker 256 cells-injected rats, and the effect was abolished by intrathecal pre-treatment with recombinant rat CCL5 (0.2 µg). These results suggest that the spinal CCL5 may be involved in the development of BCP. The findings of this study may provide an evidence for developing novel analgesic agents to treat BCP.