Ginsenoside Rb1, a principal effective ingredient of Panax notoginseng, produces pain antihypersensitivity by spinal microglial dynorphin A expression.

Panax notoginseng (Chinese ginseng, Sanqi), one of the major ginseng species, has been traditionally used to alleviate different types of chronic pain. The raw P. notoginseng powder is commonly available in China as a non-prescription drug to treat various aliments including arthritic pain. However, strong scientific evidence is needed to illustrate its pain antihypersensitive effects, effective ingredients and mechanism of action. The oral P. notoginseng powder dose-dependently alleviated formalin-induced tonic hyperalgesia, and its total ginsenosides remarkably inhibited neuropathic pain hypersensitivity. Ginsenoside Rb1, the most abundant ginsenoside of P. notoginseng, dose-dependently produced neuropathic pain antihypersensitivity. Conversely, ginsenosides Rg1, Re and notoginseng R1, the other major saponins from P. notoginseng, failed to inhibit formalin-induced tonic pain or mechanical allodynia in neuropathic pain. Ginsenoside Rb1 metabolites ginsenosides Rg3, Compound-K and protopanaxadiol also had similar antineuropathic pain efficacy to ginsenoside Rb1. Additionally, intrathecal ginsenoside Rb1 specifically stimulated dynorphin A expression which was colocalized with microglia but not neurons or astrocytes in the spinal dorsal horn and primary cultured cells. Pretreatment with microglial metabolic inhibitor minocycline, dynorphin A antiserum and specific κ-opioid receptor antagonist GNTI completely blocked Rb1-induced mechanical antiallodynia in neuropathic pain. Furthermore, the specific glucocorticoid receptor (GR) antagonist Dex-21-mesylate (but not GPR30 estrogen receptor antagonist G15) also entirely attenuated ginsenoside Rb1-related antineuropathic pain effects. All these results, for the first time, show that P. notoginseng alleviates neuropathic pain and ginsenoside Rb1 is its principal effective ingredient. Furthermore, ginsenoside Rb1 inhibits neuropathic pain by stimulation of spinal microglial dynorphin A expression following GR activation.

Mitigating Cardiotoxicity of Dendrimers: Angiotensin-(1-7) via Its Mas Receptor Ameliorates PAMAM-Induced Cardiac Dysfunction in the Isolated Mammalian Heart.

AIM: The influence of the physiochemical properties of dendrimer nanoparticles on cardiac contractility and hemodynamics are not known. Herein, we investigated (a) the effect of polyamidoamine (PAMAM) dendrimer generation (G7, G6, G5, G4 and G3) and surface chemistry (-NH2, -COOH and -OH) on cardiac function in mammalian hearts following ischemia-reperfusion (I/R) injury, and (b) determined if any PAMAM-induced cardiotoxicity could be mitigated by Angiotensin-(1-7) (Ang-(1-7), a cardioprotective agent. METHODS: Hearts isolated from male Wistar rats underwent regional I/R and/or treatment with different PAMAM dendrimers, Ang-(1-7) or its MAS receptors antagonists. Thirty minutes of regional ischemia through ligation of the left anterior descending coronary artery was followed by 30 min of reperfusion. All treatments were initiated 5 min prior to reperfusion and maintained during the first 10 min of reperfusion. Cardiac function parameters for left ventricular contractility, hemodynamics and vascular dynamics data were acquired digitally, whereas cardiac enzymes and infarct size were used as measures of cardiac injury. RESULTS: Treatment of isolated hearts with increasing doses of G7 PAMAM dendrimer progressively exacerbated recovery of cardiac contractility and hemodynamic parameters post-I/R injury. Impairment of cardiac function was progressively less on decreasing dendrimer generation with G3 exhibiting little or no cardiotoxicity. Cationic PAMAMs (-NH2) were more toxic than anionic (-COOH), with neutral PAMAMs (-OH) exhibiting the least cardiotoxicity. Cationic G7 PAMAM-induced cardiac dysfunction was significantly reversed by Ang-(1-7) administration. These cardioprotective effects of Ang-(1-7) were significantly revoked by administration of the MAS receptor antagonists, A779 and D-Pro7-Ang-(1-7). CONCLUSIONS: PAMAM dendrimers can impair the recovery of hearts from I/R injury in a dose-, dendrimer-generation-(size) and surface-charge dependent manner. Importantly, PAMAM-induced cardiotoxicity could be mitigated by Ang-(1-7) acting through its MAS receptor. Thus, this study highlights the activation of Ang-(1-7)/Mas receptor axis as a novel strategy to overcome dendrimer-induced cardiotoxicity.

Nitric oxide-releasing biomaterials for promoting wound healing in impaired diabetic wounds: State of the art and recent trends.

Impaired diabetic wounds are serious pathophysiological complications associated with persistent microbial infections including failure in the closure of wounds, and the cause of a high frequency of lower limb amputations. The healing of diabetic wounds is attenuated due to the lack of secretion of growth factors, prolonged inflammation, and/or inhibition of angiogenic activity. Diabetic wound healing can be enhanced by supplying nitric oxide (NO) endogenously or exogenously. NO produced inside the cells by endothelial nitric oxide synthase (eNOS) naturally aids wound healing through its beneficial vasculogenic effects. However, during hyperglycemia, the activity of eNOS is affected, and thus there becomes an utmost need for the topical supply of NO from exogenous sources. Thus, NO-donors that can release NO are loaded into wound healing patches or wound coverage matrices to treat diabetic wounds. The burst release of NO from its donors is prevented by encapsulating them in polymeric hydrogels or nanoparticles for supplying NO for an extended duration of time to the diabetic wounds. In this article, we review the etiology of diabetic wounds, wound healing strategies, and the role of NO in the wound healing process. We further discuss the challenges faced in translating NO-donors as a clinically viable nanomedicine strategy for the treatment of diabetic wounds with a focus on the use of biomaterials for the encapsulation and in vivo controlled delivery of NO-donors.

Hepatoprotective effect of ketoconazole in chronic liver injury model.

Ketoconazole is a first orally available anti-fungal drug which has been reported as a potent inhibitor of human cytochrome P-450. The present study was designed to examine the heptoprotective effect of ketoconazole in both in vitro and in vivo liver injury models. Hepatocyte injury was induced by 8mM CCl4 while hepatic fibrosis model was established by injecting 1 ml/kg CCl4 followed by treatment with ketoconazole. Effect of ketoconazole treatment on injured hepatocytes was determined by lactate dehydrogenase release and trypan blue assay. Analysis of ketoconazole treatment and prevention on liver fibrosis was assessed by sirius red staining, masson trichome staining, PCR and liver function tests for bilirubin and alanine transaminase (ALAT).A significant reduction (P<0.05) in LDH release and reduced number of dead cells was observed in hepatocytes treated with ketoconazole. Sirus red and masson trichome stainings showed reduced levels of collagen in both treated and preventive groups and down regulation of alpha smooth muscle actin was observed with up-regulations of MMP-2, CK-8 and CK-18. Hepatic functional assessment demonstrated reduced serum levels of bilirubin and ALAT. Treatment of fibrotic liver with ketoconazole improves hepatic microenvironment and enhanced reduction of liver injury after fibrosis. Cytochrome P-450 inhibitors seems a favored therapeutic option in attenuation of liver fibrosis.

mlCAF: Multi-Level Cross-Domain Semantic Context Fusioning for Behavior Identification.

The emerging research on automatic identification of user's contexts from the cross-domain environment in ubiquitous and pervasive computing systems has proved to be successful. Monitoring the diversified user's contexts and behaviors can help in controlling lifestyle associated to chronic diseases using context-aware applications. However, availability of cross-domain heterogeneous contexts provides a challenging opportunity for their fusion to obtain abstract information for further analysis. This work demonstrates extension of our previous work from a single domain (i.e., physical activity) to multiple domains (physical activity, nutrition and clinical) for context-awareness. We propose multi-level Context-aware Framework (mlCAF), which fuses the multi-level cross-domain contexts in order to arbitrate richer behavioral contexts. This work explicitly focuses on key challenges linked to multi-level context modeling, reasoning and fusioning based on the mlCAF open-source ontology. More specifically, it addresses the interpretation of contexts from three different domains, their fusioning conforming to richer contextual information. This paper contributes in terms of ontology evolution with additional domains, context definitions, rules and inclusion of semantic queries. For the framework evaluation, multi-level cross-domain contexts collected from 20 users were used to ascertain abstract contexts, which served as basis for behavior modeling and lifestyle identification. The experimental results indicate a context recognition average accuracy of around 92.65% for the collected cross-domain contexts.

On Curating Multimodal Sensory Data for Health and Wellness Platforms.

In recent years, the focus of healthcare and wellness technologies has shown a significant shift towards personal vital signs devices. The technology has evolved from smartphone-based wellness applications to fitness bands and smartwatches. The novelty of these devices is the accumulation of activity data as their users go about their daily life routine. However, these implementations are device specific and lack the ability to incorporate multimodal data sources. Data accumulated in their usage does not offer rich contextual information that is adequate for providing a holistic view of a user's lifelog. As a result, making decisions and generating recommendations based on this data are single dimensional. In this paper, we present our Data Curation Framework (DCF) which is device independent and accumulates a user's sensory data from multimodal data sources in real time. DCF curates the context of this accumulated data over the user's lifelog. DCF provides rule-based anomaly detection over this context-rich lifelog in real time. To provide computation and persistence over the large volume of sensory data, DCF utilizes the distributed and ubiquitous environment of the cloud platform. DCF has been evaluated for its performance, correctness, ability to detect complex anomalies, and management support for a large volume of sensory data.

Construct Validation of Three Nutrition Questions Using Health and Diet Ratings in Older Canadian Males Living in the Community.

Brief nutrition screening tools are desired for research and practice. Seniors in the Community: Risk Evaluation for Eating and Nutrition (SCREEN-II, 14 items) and the abbreviated version SCREEN-II-AB (8 items) are valid and reliable nutrition screening tools for older adults. This exploratory study used a retrospective cross-sectional design to determine the construct validity of a subset of 3 items (weight loss, appetite, and swallowing difficulty) currently on the SCREEN-II and SCREEN-II-AB tools. Secondary data on community-dwelling senior males (n = 522, mean ± SD age = 86.7 ± 3.0 years) in the Manitoba Follow-up Study (MFUS) study were available for analysis. Participants completed the mailed MFUS Nutrition Survey that included SCREEN-II items and questions pertaining to self-rated health, diet healthiness, and rating of the importance of nutrition towards successful aging as the constructs for comparison. Self-perceived health status (F = 14.7, P < 0.001), diet healthiness (ρ = 0.17, P = 0.002) and the rating of nutrition's importance to aging (ρ = 0.10, P = 0.03) were correlated with the 3-item score. Inferences were consistent with associations between these construct variables and the full SCREEN-II. Three items from SCREEN-II and SCREEN-II-AB demonstrate initial construct validity with self-perceived health status and diet healthiness ratings by older males; further exploration for criterion and predictive validity in more diverse samples is needed.

Does preoperative narcotic use adversely affect outcomes and complications after spinal deformity surgery? A comparison of nonnarcotic- with narcotic-using groups.

BACKGROUND CONTEXT: The role of preoperative (preop) narcotic use and its influence on outcomes after spinal deformity surgery are unknown. It is important to determine which patient factors and comorbidities can affect the success of spinal deformity surgery, a challenging surgery with high rates of complications at baseline. PURPOSE: To evaluate if preop narcotic use persists after spinal deformity surgery and whether the outcomes are adversely affected by preop narcotic use. STUDY DESIGN/SETTING: Retrospective evaluation of prospectively collected data. PATIENT SAMPLE: Two hundred fifty-three adult patients (230 females/23 males) undergoing primary spinal deformity surgery were enrolled from 2000 to 2009. OUTCOME MEASURES: Preoperative and postoperative (postop) narcotic use and changes in Oswestry Disability Index (ODI), Scoliosis Research Society (SRS) pain, and SRS total scores. METHODS: Preoperative, 2-year postop, and latest follow-up pain medication use were collected along with ODI, SRS pain, and SRS scores. Preoperative insurance status, surgical and hospitalization demographics, and complications were collected. All patients had a minimum 2-year follow-up (average 47.4 months). RESULTS: One hundred sixty-eight nonnarcotic (NoNarc) patients were taking no pain meds or only nonsteroidal anti-inflammatories preoperatively. Eighty-five patients were taking mild/moderate/heavy narcotics before surgery. The average age was 48.2 years for the NoNarc group versus 53.6 years for the Narc group (p<.005). There were significantly more patients with degenerative than adult scoliosis in the Narc group (47 vs. 28, p<.001; mild 19 vs. 24, p<.02; moderate 6 vs. 14, p<.0003; heavy 3 vs. 10, p<.0002). Insurance status (private/Medicare/Medicaid) was similar between the groups (p=.39). At latest follow-up, 137/156 (88%) prior NoNarc patients were still not taking narcotics whereas 48/79 (61%) prior narcotic patients were now off narcotics (p<.001). Significant postop improvements were seen in Narc versus NoNarc groups with regard to ODI (26-15 vs. 44-30.3, p<.001), SRS pain (3.36-3.9 vs. 2.3-3.38, p<.001), and overall SRS outcome (3.36-4 vs. 2.78-3.68, p<.001) scores. A comparison of change in outcome scores between the two groups showed a higher improvement in SRS pain scores for the Narc versus NoNarc group (p<.001). CONCLUSIONS: In adults with degenerative scoliosis taking narcotics a significant decrease in pain medication use was noted after surgery. All outcome scores significantly improved postop in both groups. However, the Narc group had significantly greater improvements in SRS pain scores versus the NoNarc group.

Weight Change and Clinical Outcomes Following Adult Spinal Deformity Surgery in Overweight and Obese Patients.

STUDY DESIGN: Retrospective comparative study. SUMMARY OF BACKGROUND DATA: The effect of spine surgery on postoperative weight loss or weight gain in overweight and obese spinal deformity patients is unknown. OBJECTIVE: To evaluate the postoperative outcomes and weight changes in adult patients undergoing spinal deformity surgery. MATERIALS AND METHODS: A total of 104 adult patients undergoing primary spinal deformity surgery were enrolled. All patients had a minimum 2-year follow-up (average, 50.1 months). Preoperative and latest follow-up, body mass index (BMI), Oswestry Disability Index, Scoliosis Research Society (SRS)-22 self-image and SRS outcomes scores were collected. Instrumented levels, estimated blood loss, major and minor complications, length of hospitalization, and hospital discharge status were also reviewed and compared. RESULTS: A total of 66 patients were overweight (BMI > 25-29.9; average, 26.9) (Group OW), whereas 38 patients were obese (BMI > 30; average, 33.5) (Group OB). The average age was 54.5 in Group OW and 48.6 in Group OB (p < .01). Postoperatively, significant changes were not found in the BMI for Group OW, 27.2 (26.9-27.2; p < .39), and for Group OB, 35 (33.5-35; p < .06). Postoperatively, significant improvements were seen in both groups for Oswestry Disability Index (36.1-21.8, Group OW; 44.1-24.4, Group OB; p <.001), SRS self-image (2.9-3.7, Group OW; 2.6-3.8, Group OB; p < .001) and SRS score (3.1-3.8, Group OW; 2.9-3.8, Group OB; p < .001). There were no significant differences in complications between groups. CONCLUSIONS: As a group, overweight and obese primary spinal deformity patients did not demonstrate significant weight gain or weight loss from preoperative to latest follow-up. However, both overweight and obese patients had significant improvements in outcome scores at latest follow-up and equivalent rates of complications.