Using machine learning models to improve stroke risk level classification methods of China national stroke screening.

BACKGROUND: With the character of high incidence, high prevalence and high mortality, stroke has brought a heavy burden to families and society in China. In 2009, the Ministry of Health of China launched the China national stroke screening and intervention program, which screens stroke and its risk factors and conducts high-risk population interventions for people aged above 40 years old all over China. In this program, stroke risk factors include hypertension, diabetes, dyslipidemia, smoking, lack of exercise, apparently overweight and family history of stroke. People with more than two risk factors or history of stroke or transient ischemic attack (TIA) are considered as high-risk. However, it is impossible for this criterion to classify stroke risk levels for people with unknown values in fields of risk factors. The missing of stroke risk levels results in reduced efficiency of stroke interventions and inaccuracies in statistical results at the national level. In this paper, we use 2017 national stroke screening data to develop stroke risk classification models based on machine learning algorithms to improve the classification efficiency. METHOD: Firstly, we construct training set and test sets and process the imbalance training set based on oversampling and undersampling method. Then, we develop logistic regression model, Naïve Bayesian model, Bayesian network model, decision tree model, neural network model, random forest model, bagged decision tree model, voting model and boosting model with decision trees to classify stroke risk levels. RESULT: The recall of the boosting model with decision trees is the highest (99.94%), and the precision of the model based on the random forest is highest (97.33%). Using the random forest model (recall: 98.44%), the recall will be increased by about 2.8% compared with the method currently used, and several thousands more people with high risk of stroke can be identified each year. CONCLUSION: Models developed in this paper can improve the current screening method in the way that it can avoid the impact of unknown values, and avoid unnecessary rescreening and intervention expenditures. The national stroke screening program can choose classification models according to the practice need.

Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice by downregulating collagen deposition.

This study aimed to explore the protective effects of madecassoside (Mad), a triterpenoid saponin isolated from Centella asiatica herbs, on experimental pulmonary fibrosis (PF) and underlying mechanisms. PF model was established in mice by endotracheal instillation with bleomycin (5 mg/kg). Mice were orally administered with Mad (10, 20, 40 mg/kg) and prednisone (5 mg/kg) for 7 or 21 days. Mad (20, 40 mg/kg) significantly improved lung pathological changes and reduced collagen deposition. In the aspect of collagen synthesis, Mad (20, 40 mg/kg) reduced the expressions of α-smooth muscle actin and transforming growth factor-ß1 (TGF-ß1), and inhibited the phosphorylations of Smad2 and Smad3 in the lung tissues. However, in vitro, Mad showed little effect on TGF-ß1-induced phosphorylation of either Smad2 or Smad3 in primary mouse lung fibroblasts. Moreover, Mad (20, 40 mg/kg) attenuated oxidative damage and inflammation presented at the early stage of PF, evidenced by reduced total leukocytes in the bronchoalveolar lavage fluid, decreased myeloperoxidase activity and malondialdehyde level, and increased super-oxide dismutase activity and glutathione level in lung tissues. On the other hand, Mad (40 mg/kg) elevated the matrix metalloproteinase 1/tissue inhibitor of metalloproteinase 1 ratio in lung tissues of PF mice mainly by downregulating tissue inhibitor of metalloproteinase 1 expression. The present study demonstrated that Mad can ameliorate PF by preventing the deposition of extracellular matrix, which might be achieved mainly through attenuating inflammation and oxidative stress and consequent TGF-ß1 overexpression.

Preparation of a novel CSM@ZIF-67 composite microsphere to facilitate Congo red adsorption from dyeing wastewater.

ABSTRACTChitosan (CS) is commonly used as an adsorbent for wastewater treatment because of its low cost, strong adsorption properties, and high availability of raw materials required for its production. However, CS exhibits limited adaptability to pH, poor mechanical properties, and high swelling in aqueous media; these limitations restrict its widespread use. To address these issues, herein, zeolitic imidazolate framework-67 (ZIF-67) is loaded onto crosslinked CS microspheres (CSM) to prepare CSM@ZIF-67, a composite adsorbent. Next, the CSM@ZIF-67 is applied to the treatment of Congo red (CR) dye, which is typically present in printing and dyeing wastewater. The results demonstrate that the in situ synthesis of metal-organic frameworks (MOFs) on CSM improve the dispersion of MOFs and preserve the morphology of the MOFs. The adsorption equilibrium of CSM@ZIF-67 is reached within 150 min, and its adsorption capacity is as high as 538.4 mg/g at a pH of 9 and temperature of 25 °C. The CR adsorption process is consistent with the pseudo-second-order kinetic and Langmuir isotherm models, thus revealing that chemisorption is the primary rate-limiting step, and the pollutants are adsorbed on the adsorbent surface in a monolayer. Experiments on material cycling and regeneration performance reveal that the removal efficiency of CSM@ZIF-67 remains above 90%, even after five rounds of adsorption. CSM@ZIF-67 has abundant functional groups and adsorption sites and can efficiently remove CR through mutual interactions between the metal coordination effect, π-π conjugation, hydrogen bonding, and electrostatic interactions.

Performance of anammox enchanced by pulsed electric fields under added organic carbon sources using integrated network and metagenomics analyses.

This paper aims to investigate the function of a pulsed electric field (PEF) in the anaerobic ammonia oxidation (anammox) process after adding certain chemical oxygen demand (COD) through integrated network and metagenomics analyses. The findings showed that the presence of COD was detrimental to anammox, but PEF could significantly reduce the adverse effect. The total nitrogen removal in the reactor for applying PEF was 16.99% higher on average than the reactor for only dosing COD. Additionally, PEF upgraded the abundance of anammox bacteria subordinate to the phylum Planctomycetes by 9.64%. The analysis of molecular ecological networks promulgated that PEF resulted in an increase in network scale and topology complexity, thereby boosting the potential collaboration of the communities. Metagenomics analyses demonstrated that PEF dramatically promoted anammox central metabolism in the presence of COD, specifically enhancing pivotal N functional genes (hzs, hdh, amo, hao, nas, nor and nos).

A novel wet-scrubbing process using Fe(VI) for simultaneous removal of SO2 and NO.

The objective of this work was to develop a novel wet-scrubbing process using Fe(VI) for the simultaneous removal of gaseous NO and SO(2). The oxidation of SO(2) and NO with Fe(VI) was studied in aqueous solution at alkaline pH (9.0-11.0). A stoichiometric molar ratio for NO and SO(2) oxidation with Fe(VI) was determined to be nearly 3.0. Sulfate and nitrate was identified as final products by ion chromatography from the reaction at pH 9.0-11.0. The feasibility of simultaneous removal of multiple gas pollutants with the continuous feeding of ferrate in lab-scale was investigated from the view of industrial application. It was found that the removal efficiency of NO and SO(2) was enhanced with the increase of Fe(VI) concentration, more than 90% NO removal efficiency and 100% SO(2) removal efficiency were achieved by wet-scrubbing process using Fe(VI) at room temperature and ambient atmosphere. The results demonstrate that Fe(VI) could be an effective wet-scrubbing agent for the simultaneous removal of NO and SO(2).

Construction of Simulation Platform for Chinese Stroke Economic Burden Based on the National Screening Data.

With the characteristics of high incidence, high prevalence and high mortality, stroke has a serious impact on residents' health and imposes a heavy ecomomic burden on China. In order to simulate the economic burden of stroke in the next 20 years, we construct a simulation platform for Chinese stroke economic burden based on the national stroke screening data. We use the Leslie model for population prediction and the equilibrium model to simulate the stroke economic burden in the platform. The platform constructed in this study can dynamically simulate the stroke economic burden during 2020-2040 by computing the incidence, prevelance and mortality rates from the national stroke screening data or as customized by the user. Based on this platform, we can further develop a warning mechanism at the national level, and provide a guide for the planning and allocation of national health resources.

Using machine learning models to classify stroke risk level based on national screening data.

With the character of high incidence, high prevalence and high mortality, stroke has brought a heavy burden to families and society in China. In 2009, the Ministry of Health of China launched the China national stroke screening and intervention program, which screens stroke risk factors and conducts high-risk population interventions for people aged over 40 years old all over China. In this program, stroke risk factors include hypertension, diabetes, dyslipidemia, atrial fibrillation, smoking, lack of exercise, apparently overweight or obese and family history of stroke. People with more than two risk factors or with a history of stroke or transient ischemic attack (TIA) are considered as high-risk. However, it is impossible for this criterion to classify stroke risk level for people with "unknown" values in the fields of risk factors. The missing of stroke risk levels results in reduced efficiency of stroke interventions and inaccuracies in the statistical results at the national level. In this paper, firstly, we construct the training set and test set and process the imbalanced training set based on oversampling and undersampling method. Then, we develop logistic regression model, decision tree model, neural network model and random forest model for stroke risk classification, and evaluate these models based on the recall and precision. The results show that the model based on random forest achieves best performance considering recall and precision. The models constructed in this paper can improve the screening efficiency and avoid unnecessary rescreening and intervention expenditures.

[Exploration on the application of Qimen (LR 14) in Treatise on Febrile Diseases].

In Treatise on Febrile Diseases, ZHANG Zhongjing had used Qimen (LR 14) for the most times compared with other acupoints among the limited numbers of acupuncture prescriptions. Qimen (LR 14) is the front-mu point of the liver meridian, acting on smoothing liver qi and regulating qi activity. It is commonly used to treat the disorders caused by retarded circulation of qi and blood, such as distension and pain of the hypochondriac region and masses. Based on the opening-closing-pivot theory of the six meridians, the specificity of the running course of the jueyin meridian and the property of Qimen (LR 14), the mechanisms of Qimen (LR 14) were analyzed on the treatment of febrile diseases, aiming to enhance the considerations and application of this points in clinical practice and contribute to the further understanding of ZHANG Zhongjing' s academic thoughts on the syndrome differentiation in the treatment of diseases.

Paleoseismic study of the Kamishiro Fault on the northern segment of the Itoigawa-Shizuoka Tectonic Line, Japan.

The Mw 6.2 (Mj 6.8) Nagano (Japan) earthquake of 22 November 2014 produced a 9.3-km long surface rupture zone with a thrust-dominated displacement of up to 1.5 m, which duplicated the pre-existing Kamishiro Fault along the Itoigawa-Shizuoka Tectonic Line (ISTL), the plate-boundary between the Eurasian and North American plates, northern Nagano Prefecture, central Japan. To characterize the activity of the seismogenic fault zone, we conducted a paleoseismic study of the Kamishiro Fault. Field investigations and trench excavations revealed that seven morphogenic paleohistorical earthquakes (E2-E8) prior to the 2014 Mw 6.2 Nagano earthquake (E1) have occurred on the Kamishiro Fault during the last ca. 6000 years. Three of these events (E2-E4) are well constrained and correspond to historical earthquakes occurring in the last ca. 1200 years. This suggests an average recurrence interval of ca. 300-400 years on the seismogenic fault of the 2014 Kamishiro earthquake in the past 1200 years. The most recent event prior to the 2014 earthquakes (E1) is E2 and the penultimate and antepenultimate faulting events are E3 and E4, respectively. The penultimate faulting event (E3) occurred during the period of AD 1800-1400 and is associated with the 1791 Mw 6.8 earthquake. The antepenultimate faulting event (E4) is inferred to have occurred during the period of ca. AD 1000-700, likely corresponding to the AD 841 Mw 6.5 earthquake. The oldest faulting event (E8) in the study area is thought to have occurred during the period of ca. 5600-6000 years. The throw rate during the early Holocene is estimated to be 1.2-3.3 mm/a (average, 2.2 mm/a) with an average amount of characteristic offset of 0.7-1.1 m produced by individual event. When compared with active intraplate faults on Honshu Island, Japan, these slip rates and recurrence interval estimated for morphogenic earthquakes on the Kamishiro Fault along the ISTL appear high and short, respectively. This indicates that present activity on this fault is closely related to seismic faulting along the plate boundary between the Eurasian and North American plates.

[Pleomorphic adenoma of the nasal septum: a case report].

We report a rare case of pleomorphic adenoma arising from the nasal septum. A 37-year-old woman presented with a 1-year-history of right-sided occasional epistaxis. Computed tomographic scans revealed an oval mass in the right nasal cavity. The tumor was removed endoscopically with endonasal approach. The microscopic finding showed numbers of myoepithelial cells and duct-like structures consisting of loose myxoid stroma. This lesion had histological characteristics of a pleomorphic adenoma, and this was confirmed by immunohistochemical expression of cytokeratin, S-100 protein and SMA. Her post-operative course was uneventful, and she is currently free from the disease 1.5 years after surgery.

[Effects of electroacupuncture at "Neiguan" (PC 6) on sodium channel-related proteins in rats with ischemic myocardial injury].

OBJECTIVE: To explore the protective mechanism of electroacupuncture (EA) at "Neiguan" (PC 6) on ischemic myocardial injury, and to explain the response patterns and characteristics of the specific effect of acupoints along meridians in sodium channel in the level of cardiac organ. METHODS: A total of 60 SPF male rats were randomly divided into a blank group, a model group, a non-acupoint group, a Neiguan group and a Lieque group, 12 cases in each one. Except the blank group, rats in the remaining group were treated with subcutaneous injection of isoprenaline to establish the model of myocardial ischemia. Rats in the Neiguan group, Lieque group and non- acupoint group were treated with EA, dilatational wave, with a frequency of 2 Hz/20 Hz. The intensity was 2-3 mA. The needles were retained for 20 min per time, once a day for consecutive 7 days. In the blank group and control group, the rats were grasped and fixed at the treating time each day. The western-blot method was used to test the expression of voltage-gated sodium channel alpha subunit (Nav 1.5), protein tyrosine kinase (PTKs) and protein tyrosine phosphatase (PTPs). RESULTS: The expression of Nav 1.5 and PTKs in the model group was lower than that in the blank group (both P<0. 01); the expression in the Neiguan group and Lieque group was higher than that in the model group (all P < 0.01); the expression of Nav 1.5 and PTKs in the Neiguan group was higher than that in the Lieque group (both P < 0.01). The expression of PTPs in the model group and non-acupoint group was higher than that in the blank group (both P < 0.01); the expression of PTPs in the Neiguan group and Lieque group was significantly down-regulated, which was lower than the model group (both P < 0.01); the down-regulation in the Neiguan group was significantly different from that in the Lieque group (P < 0.05). CONCLUSION: EA at "Neiguan" (PC 6), by down-regulating the expression of PTPs, up-regulating the expression of Nav 1.5 and PTKs, is likely to achieve the aim of regulation on sodium channel activity and calcium overload, further to improve myocardial ischemia, which provides experimental basis for the theory of the specific effect of acupoints along meridians.

[Clinical observation of post-stroke upper limb spasmodic hemiplegia treated with relaxing needling technique combined with wheat-grain moxibustion].

OBJECTIVE: To compare the differences in the clinical efficacy on post-stroke upper limb spasmodio hemiplegia among the combined therapy of relaxing needling (Huici) technique combined with wheat-grain moxibustion, simple relaxing needling and conventional acupuncture. METHODS: Ninety patients were-randomized into a group with the combined therapy of relaxing needling technique combined with wheat-grain moxibustion (a combined therapy group), a simple relaxing needling group and a conventional acupuncture group, 30 cases in each group. In the combined therapy group, the relaxing needling technique was used in combination with wheat-grain moxibustion. The relaxing needling technique was applied to Jianyu (LI 15), Quchi (LI 11), Shousanli (LI 10), etc. The wheat-grain moxibustion was applied to Qihai (CV 6), Guanyuan (CV 4), Mingmen (GV 4), etc. In thel simple relaxing needling group, the relaxing needling technique was used simply. In the conventional acupuncture group, the conventional lifting, thrusting and rotating technique with filiform needle was adopted at the same acupoints as the simple relaxing needling group. The treatment was given once every day; 6 treatments made one session. Totally 4 sessions were required, with 1 day at intervals. The modified Ashworth scale (MAS), Fugl-Meyer assessment (FMA) and Barthel index (BD were adopted to assess the upper limb muscle tension, motor functioni and daily life activity. RESULTS: After treatment, MAS score was all reduced as compared with that before treatment in each group, and FMA score and BI score were increased as compared with those before treatment (all P<0.01). MAS score in the combined therapy group was lower than that in either the simple relaxing needling group or the conventional acupuncture group (both P<0.01), and the score in the simple relaxing needling group was lower than that in the conventional acupuncture group (P<0.05). FMA score and BI score in the combined therapy group were higher than those in the simple relaxing needling group and the conventional acupuncture group (both P<0.01). FMA score in the simple relaxing needleing group was higher than that the Enventional acupuncture group (P<0.05). The total effective rate in the combined therapy group was 93.3% (28/30), higher; than 86.7% (26/30) in the simple relaxing needling group (P<0.01), and 83.8% (25/30) in the conventionaP acupuncture group (P<0.01). CONCLUSION: The combined therapy of relaxing needling technique and wheat-grain moxibustion achieves more satisfactory efficacy on post-stroke upper limb spasmodic hemiplegia compared with the simple relaxing needling and conventional acupuncture.

[Correlation between heel vessel and human balance function].

The heel vessel belongs to the eight extra meridians in human meridian system, which is closely related to the human motion function. Balance function plays an essential role in successful completion of activities in daily life, so the physiological function and pathology of heel vessel as well as human balance function are analyzed, and from the aspect of running course of heel vessel and syndrome, the correlation between heel vessel and human balance function is explored, and the application status of acupoints related to heel vessel for balance dysfunction is introduced. It is believed that heel vessel is closely related to human balance function, especially the motion regulation mechanisms of balance function, and it is hoped that new ideas and methods can be provided for acupuncture treatment for the balance function disorders.

[Effect of electroacupuncture stimulation of "Neiguan" (PC 6) on expression of alpha- and beta-subunit proteins of voltage-gated sodium channels in rats with myocardial ischemia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Neiguan" (PC 6) on expression of sodium (Nav) channel α-subunit 1.5 and Nav ß-subunits ß 1-ß 4 (the known myocardial sodium channel proteins) in acute myocardial ischemia (AMI) rats so as to explore its mechanisms underlying protection of ischemic myocardium. METHODS: Sixty SD male rats were randomly divided into normal control, AMI model, Neiguan (PC 6), Lieque (LU 7) and non-acupoint groups. The AMI model was established by intravenous injection of Isoprenaline (85 mg/kg) once daily for 2 days. Myocardial Nav 1.5 and Nav ß 1, ß 2, ß 3, ß 4 protein expression levels were detected by Western blot. RESULTS: In comparison with the control group, myocardial Nav 1.5, ß 1, ß 2, ß 3 and ß 4 protein expression levels were significantly down-regulated in the AMI model group (P<0.01). After EA stimulation, compared with the model group, the expression levels of Nav 1.5, Nav ß 1, ß 2, ß 3 and ß 4 protein expression levels were significantly up-regulated in the Neiguang (PC 6) and Lieque (LU 7) groups (P<0.01) rather than in the non-acupoint group (P>0.05). There was no statistical significance between the Neiguan (PC 6) and Lieque (LU 7) groups in ß 4 protein expression level (P>0.05). CONCLUSION: EA stimulation of both PC 6 and LU 7 can significantly reverse AMI-induced down-regulation of myocardial Nav 1.5, ß 1, ß 2, ß 3 and ß 4 protein expression levels in AMI rats, which might contribute to its function in improving AMI by reducing calcium overload.

Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1-13) or MK-801 in a nerve-ligation model of peripheral neuropathy.

Neuropathic pains arising from peripheral nerve injury can result in increased sensitivity to both noxious and non-noxious stimuli and are accompanied by a number of neuroplastic alterations at the level of the spinal cord including upregulation of neurotransmitters including dynorphin, cholecystokinin and neuropeptide Y. Additionally, such pain states appear to be associated with activation of excitatory amino acid receptors including the N-methyl-D-aspartate (NMDA) receptor. Neuropathic pains have often been classified as 'opioid resistant' in both clinical and laboratory settings. As it is known that dynorphin produces 'non-opioid' effects through interaction with NMDA receptors and this peptide is upregulated after peripheral nerve injury, the present studies were undertaken to determine the possible importance of this substance in the neuropathic state. Nerve injury was produced in rats by tight ligation of the L5 and L6 spinal roots of the sciatic nerve. Catheters were inserted for the intrathecal (i.t.) delivery of drug to the lumbar spinal cord. Tactile allodynia was determined by measuring responses to probing the plantar surface of the affected limb with von Frey filaments, and acute nociception was determined in the 55 degrees C hot-water tail-flick test in nerve-ligated and sham-operated subjects. Intrathecal administration of MK-801 or antisera to dynorphin A (1-13) did not alter the tactile allodynia associated with nerve-ligation injury or the baseline tail-flick latency in either sham-operated or nerve-injured animals. As previously reported, i.t. morphine did not alter tactile allodynia and showed reduced potency and efficacy to block the tail-flick reflex in nerve-injured animals. Co-administration, however, of i.t. morphine with MK-801, or i.t. antisera to dynorphin A (1-13) given prior to morphine elicited both a full antiallodynic response and a complete block of the tail-flick reflex in nerve-injured animals. These results suggest that tonic activation of NMDA receptors, following peripheral nerve injury, is involved with the attenuation of the effectiveness of spinal morphine in a model of neuropathic pain. Additionally, this tonic NMDA activity may be mediated, in part, by increased levels of endogenous dynorphin associated with peripheral nerve injury.

Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8.

Neuropathic pain is a debilitating chronic syndrome that often arises from injuries to peripheral nerves. Such pain has been hypothesized to be the result of an aberrant expression and function of sodium channels at the site of injury. Here, we show that intrathecal administration of specific antisense oligodeoxynucleotides (ODN) to the peripheral tetrodotoxin (TTX)-resistant sodium channel, NaV1.8, resulted in a time-dependent uptake of the ODN by dorsal root ganglion (DRG) neurons, a selective "knock-down" of the expression of NaV1.8, and a reduction in the slow-inactivating, TTX-resistant sodium current in the DRG cells. The ODN treatment also reversed neuropathic pain induced by spinal nerve injury, without affecting non-noxious sensation or response to acute pain. These data provide direct evidence linking NaV1.8 to neuropathic pain. As NaV1.8 expression is restricted to sensory neurons, this channel offers a highly specific and effective molecular target for the treatment of neuropathic pain.

Extranodal follicular dendritic cell sarcoma of the soft palate: a case report.

Follicular dentritic cell sarcoma (FDCS) is an extremely rare malignant neoplasm arising from the accessory cells of the lymph nodes, the follicular dendritic cells. They commonly occur in the lymph nodes, but have also been reported at extranodal sites. Because of its rarity, FDCS is not easily to make a diagnosis by clinicians or pathologists. Herein, we report a soft palate tumor in a 59-year-old female, with a history of tonsillectomy. Pharynx MRI scan revealed a 4.7×3.0×3.5 cm mass at the right side of the parapharyngeal space. The pathology results returned as Follicular dentritic cell sarcoma. The patient underwent a tumorectomy and adjuvant postoperative radiotherapy. The patient was free of disease 1 year after the end of the treatment. The FDCS is an infrequent nonlymphoid malignant tumor accounting for less than 1% of all head and neck tumors. The immunohistochemical technique is essential for accurately identifying this class of tumour.

INCB38579, a novel and potent histamine H4 receptor small molecule antagonist with anti-inflammatory pain and anti-pruritic functions.

The histamine H4 receptor mediates several histamine-induced cellular functions of leukocytes, including cell migration and cytokine production. Recent studies suggest that histamine signaling through the histamine H4 receptor can also have anti-pruritic and anti-nociceptive functions. 1-(7-(2-amino-6-(4-methylpiperazin-1-yl) pyrimidin-4-yl)-3, 4-dihdroisoquinolin-2(1H)-yl)-2-cyclopentylethanone (INCB38579) is a novel small molecule antagonist of the human and rodent histamine H4 receptors with at least 80-fold selectivity over the human histamine H1, H2 and H3 receptors, and has good pharmacokinetic properties in rats and mice. The compound is potent in inhibiting histamine binding to and signaling through the recombinant human, mouse and rat histamine H4 receptors and blocks the histamine-induced migration of human and mouse dendritic cells, as well as the cell shape change and migration of human eosinophils. INCB38579 and histamine may have separate but overlapping binding sites on the human histamine H4 receptor. This novel inhibitor is efficacious when evaluated in two previously established in vivo models for histamine H4 receptor activity (histamine-induced itch in mice and carrageenan-induced acute inflammatory pain in rats). When examined in formalin-induced pain models, INCB38579 significantly reduces the sustained inflammatory pain experienced by rats and mice. A good correlation between the protein binding adjusted potency from in vitro studies and its analgesic effect in vivo was observed. These results suggest that INCB38579 can serve as a useful tool for pharmacologic characterization of the histamine H4 receptor and further support the hypothesis that targeting the histamine H4 receptor may provide new therapeutic agents for various chronic inflammatory diseases, including inflammatory pain.

Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance.

A considerable body of evidence implicates endogenous nerve growth factor (NGF) in conditions in which pain is a prominent feature, including neuropathic pain. However, previous studies of NGF antagonism in animal models of neuropathic pain have examined only the prevention of hyperalgesia and allodynia after injury, whereas the more relevant issue is whether treatment can provide relief of established pain, particularly without tolerance. In the current work, we studied the effects of potent, neutralizing anti-NGF antibodies on the reversal of tactile allodynia and thermal hyperalgesia in established models of neuropathic and inflammatory pain in rats and mice. In the complete Freund's adjuvant-induced hind-paw inflammation, spinal nerve ligation and streptozotocin-induced neuropathic pain models, a single intraperitoneal injection of a polyclonal anti-NGF antibody reversed established tactile allodynia from approximately day 3 to day 7 after treatment. Effects on thermal hyperalgesia were variable with a significant effect observed only in the spinal nerve ligation model. In the mouse chronic constriction injury (CCI) model, a mouse monoclonal anti-NGF antibody reversed tactile allodynia when administered 2 weeks after surgery. Repeated administration of this antibody to CCI mice for 3 weeks produced a sustained reversal (days 4 to 21) of tactile allodynia that returned 5 days after the end of dosing. In conclusion, NGF seems to play a critical role in models of established neuropathic and inflammatory pain in both rats and mice, with no development of tolerance to antagonism. Antagonists of NGF, such as fully human monoclonal anti-NGF antibodies, may have therapeutic utility in analogous human pain conditions.