Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis

Background

Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease.

Methods

We induced OA via intra-articular mono-iodoacetate (MIA) injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2) on pain behavior, disease progression, and ASIC3 expression in knee joint afferents.

Results

OA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia). ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase.

Conclusions

Local ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression.     

Chronic oral or intraarticular administration of docosahexaenoic acid reduces nociception and knee edema and improves functional outcomes in a mouse model of Complete Freund’s Adjuvant–induced knee arthritis

Introduction

Clinical and preclinical studies have shown that supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs) reduce joint destruction and inflammation present in rheumatoid arthritis (RA). However, the effects of individual ω-3 PUFAs on chronic arthritic pain have not been evaluated to date. Thus, our aim in this study was to examine whether purified docosahexaenoic acid (DHA, an ω-3 PUFA) reduces spontaneous pain-related behavior and knee edema and improves functional outcomes in a mouse model of knee arthritis.

Methods

Unilateral arthritis was induced by multiple injections of Complete Freund’s Adjuvant (CFA) into the right knee joints of male ICR adult mice. Mice that received CFA injections were then chronically treated from day 15 until day 25 post–initial CFA injection with oral DHA (10, 30 and 100 mg/kg daily) or intraarticular DHA (25 and 50 μg/joint twice weekly). Spontaneous flinching of the injected extremity (considered as spontaneous pain-related behavior), vertical rearing and horizontal exploratory activity (considered as functional outcomes) and knee edema were assessed. To determine whether an endogenous opioid mechanism was involved in the therapeutic effect of DHA, naloxone (NLX, an opioid receptor antagonist, 3 mg/kg subcutaneously) was administered in arthritic mice chronically treated with DHA (30 mg/kg by mouth) at day 25 post–CFA injection.

Results

The intraarticular CFA injections resulted in increasing spontaneous flinching and knee edema of the ipsilateral extremity as well as worsening functional outcomes as time progressed. Chronic administration of DHA, given either orally or intraarticularly, significantly improved horizontal exploratory activity and reduced flinching behavior and knee edema in a dose-dependent manner. Administration of NLX did not reverse the antinociceptive effect of DHA.

Conclusions

To the best of our knowledge, this report is the first to demonstrate DHA’s antinociceptive and anti-inflammatory effects as individual ω-3 PUFAs following sustained systemic and intraarticular administration in a mouse model of CFA-induced knee arthritis. The results suggest that DHA treatment may offer a new therapeutic approach to alleviate inflammation as well as a beneficial effect on pain-related functional disabilities in RA patients.     

Evaluation of Anti-Hyperalgesic and Analgesic Effects of Two Benzodiazepines in Human Experimental Pain: A Randomized Placebo-Controlled Study

Background and Aims

Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABA_A-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.

Methods

In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.

Results

For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.

Conclusions

Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABA_A-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01011036","term_id":"NCT01011036"}}NCT01011036     

Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial

Introduction

Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy.

Methods

Patients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis.

Results

We randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by −0.08 on MTX versus −0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain −1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia).

Conclusions

The results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity.

Trial registration

EudraCT No: 2007-003479-37. Registered 26 April 2008     

Increased Brain White Matter Axial Diffusivity Associated with Fatigue,Pain and Hyperalgesia in Gulf War Illness

Background

Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction.

Methods

Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs.

Results

Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis.

Conclusion

The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.     

Antinociceptive interaction of (±)-CPP and propentofylline in monoarthritic rats

Introduction

Multiple studies have shown that glial cells of the spinal cord, such as astrocytes and microglia, have close contact with neurons, suggesting the term tripartite synapse. In these synapses, astrocytes surrounding neurons contribute to neuronal excitability and synaptic transmission, thereby increasing nociception and thus the persistence of chronic pain. Conversely, the N-methyl-D-aspartate (NMDA) receptor is crucial in the generation and maintenance of chronic pain. It has multiple sites of modulation. One is the site of recognition of extracellular neurotransmitter (glutamate), which can be blocked by competitive antagonists such as (3-(2-carboxipiperazin-4)1-propyl phosphonic acid), (±)-CPP, resulting in a blockade of the calcium current and thus the intracellular transduction process. In the present study, we investigated whether the potential antinociceptive effect of glial inhibition produced by propentofylline (PPF) can be enhanced when combined with an NMDA-receptor inhibitor such as (±)-CPP.

Methods

We used Sprague-Dawley monoarthritic rats. The monoarthritis was induced by injection of complete Freund adjuvant in the right tibiotarsal joint. Four weeks later, rats were treated with PPF (1, 10, 30, and 100 μg/10 μl) intrathecally (i.t.) for 10 days, injected once with (±)-CPP (2.5, 5, 12.5, 25, 50, and 100 μg/10 μl, i.t.), or both treatments combined. The antinociceptive effect was evaluated on day 11 for PPF and immediately to (±)-CPP, by assessing the vocalization threshold to mechanical stimulation of the arthritic paw.

Results

The data indicate that intrathecal administration of increasing concentrations of (±)-CPP or PPF produced a significant dose-dependent antinociceptive effect with respect to monoarthritic rats receiving saline. The linear regression analysis showed that the dose that produces 30% of maximal effect (ED₃₀) for i.t. (±)-CPP was 3.97 μg, and 1.42 μg for i.t. PPF. The administration of the PPF and (±)-CPP combination in fixed proportions of ED₃₀ produced a dose-dependent antinociceptive effect, showing an interaction of the supraadditive type.

Conclusions

The results suggest that glia inhibitors can synergically potentiate the effect of glutamate blockers for the treatment of chronic inflammatory pain.     

Stress-Induced Allodynia – Evidence of Increased Pain Sensitivity in Healthy Humans and Patients with Chronic Pain after Experimentally Induced Psychosocial Stress

Background

Experimental stress has been shown to have analgesic as well as allodynic effect in animals. Despite the obvious negative influence of stress in clinical pain conditions, stress-induced alteration of pain sensitivity has not been tested in humans so far. Therefore, we tested changes of pain sensitivity using an experimental stressor in ten female healthy subjects and 13 female patients with fibromyalgia.

Methods

Multiple sensory aspects of pain were evaluated in all participants with the help of the quantitative sensory testing protocol before (60 min) and after (10 and 90 min) inducing psychological stress with a standardized psychosocial stress test (“Trier Social Stress Test”).

Results

Both healthy subjects and patients with fibromyalgia showed stress-induced enhancement of pain sensitivity in response to thermal stimuli. However, only patients showed increased sensitivity in response to pressure pain.

Conclusions

Our results provide evidence for stress-induced allodynia/hyperalgesia in humans for the first time and suggest differential underlying mechanisms determining response to stressors in healthy subjects and patients suffering from chronic pain. Possible mechanisms of the interplay of stress and mediating factors (e.g. cytokines, cortisol) on pain sensitivity are mentioned. Future studies should help understand better how stress impacts on chronic pain conditions.     

The Inhibition of Subchondral Bone Lesions Significantly Reversed the Weight-Bearing Deficit and the Overexpression of CGRP in DRG Neurons,GFAP and Iba-1 in the Spinal Dorsal Horn in the Monosodium Iodoacetate Induced Model of Osteoarthritis Pain

Background

Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA). Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain.

Methods

Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA) into the rat knee joint. Zoledronic acid (ZOL), a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG), and spinal glial activation status using glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling.

Results

MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected.

Conclusions

The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.     

Osteopontin Level in Synovial Fluid Is Associated with the Severity of Joint Pain and Cartilage Degradation after Anterior Cruciate Ligament Rupture

Objective

To explore the molecular function of Osteopontin (OPN) in the pathogenesis of human OA, we compared the expression levels of OPN in synovial fluid with clinical parameters such as arthroscopic observation of cartilage damage and joint pain after joint injury.

Methods

Synovial fluid was obtained from patients who underwent anterior cruciate ligament (ACL) reconstruction surgery from 2009 through 2011 in our university hospital. The amounts of intact OPN (OPN Full) and it’s N-terminal fragment (OPN N-half) in synovial fluid from each patient were quantified by ELISA and compared with clinical parameters such as severity of articular cartilage damage (TMDU cartilage score) and severity of joint pain (Visual Analogue Scale and Lysholm score).

Results

Within a month after ACL rupture, both OPN Full and N-half levels in patient synovial fluid were positively correlated with the severity of joint pain. In contrast, patients with ACL injuries greater than one month ago felt less pain if they had higher amounts of OPN N-half in synovial fluid. OPN Full levels were positively correlated with articular cartilage damage in lateral tibial plateau.

Conclusion

Our data suggest that OPN Full and N-half have distinct functions in articular cartilage homeostasis and in human joint pain.     

Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial

Background

Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST).

Methods

This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups.

Results

64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation.

Conclusion

Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00755573","term_id":"NCT00755573"}}NCT00755573     

Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis

Introduction

Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.

Methods

OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.

Results

Behavioural hypersensitivity ipsilateral to knee injury was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind limb weight-bearing asymmetry in MIA-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight-bearing asymmetry was not corrected.

Conclusions

Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent. This suggests that, if used in OA patients, LCM may allow physiological transmission but suppress secondary hyperalgesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation.     

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain

Background

Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated.

Results

The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED₅₀ was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes.

Conclusion

These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.     

A Novel and Selective Poly (ADP-Ribose) Polymerase Inhibitor Ameliorates Chemotherapy-Induced Painful Neuropathy

Background

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.

Results

An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.

Conclusion

Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.     

Interaction of hyperalgesia and sensory loss in complex regional pain syndrome type I (CRPS I)

Background

Sensory abnormalities are a key feature of Complex Regional Pain Syndrome (CRPS). In order to characterise these changes in patients suffering from acute or chronic CRPS I, we used Quantitative Sensory Testing (QST) in comparison to an age and gender matched control group.

Methods

61 patients presenting with CRPS I of the upper extremity and 56 healthy subjects were prospectively assessed using QST. The patients'' warm and cold detection thresholds (WDT; CDT), the heat and cold pain thresholds (HPT; CPT) and the occurrence of paradoxical heat sensation (PHS) were observed.

Results

In acute CRPS I, patients showed warm and cold hyperalgesia, indicated by significant changes in HPT and CPT. WDT and CDT were significantly increased as well, indicating warm and cold hypoaesthesia. In chronic CRPS, thermal hyperalgesia declined, but CDT as well as WDT further deteriorated. Solely patients with acute CRPS displayed PHS. To a minor degree, all QST changes were also present on the contralateral limb.

Conclusions

We propose three pathomechanisms of CRPS I, which follow a distinct time course: Thermal hyperalgesia, observed in acute CRPS, indicates an ongoing aseptic peripheral inflammation. Thermal hypoaesthesia, as detected in acute and chronic CRPS, signals a degeneration of A-delta and C-fibres, which further deteriorates in chronic CRPS. PHS in acute CRPS I indicates that both inflammation and degeneration are present, whilst in chronic CRPS I, the pathomechanism of degeneration dominates, signalled by the absence of PHS. The contralateral changes observed strongly suggest the involvement of the central nervous system.     

Coenzyme Q10 Ameliorates Pain and Cartilage Degradation in a Rat Model of Osteoarthritis by Regulating Nitric Oxide and Inflammatory Cytokines

Objective

To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA).

Materials and Methods

OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry.

Results

Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment.

Conclusion

CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.     

Associations between Quantitative Mobility Measures Derived from Components of Conventional Mobility Testing and Parkinsonian Gait in Older Adults

Objective

To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait.

Methods

During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS).

Results

In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2^nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor.

Interpretation

Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults.     

Relation of Pulse Pressure to Long-Distance Gait Speed in Community-Dwelling Older Adults: Findings from the LIFE-P Study

Background

Reduced gait speed is associated with falls, late-life disability, hospitalization/institutionalization and cardiovascular morbidity and mortality. Aging is also accompanied by a widening of pulse pressure (PP) that contributes to ventricular-vascular uncoupling. The purpose of this study was to test the hypothesis that PP is associated with long-distance gait speed in community-dwelling older adults in the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study.

Methods

Brachial blood pressure and 400-meter gait speed (average speed maintained over a 400-meter walk at “usual” pace) were assessed in 424 older adults between the ages of 70–89 yrs at risk for mobility disability (mean age = 77 yrs; 31% male). PP was calculated as systolic blood pressure (BP) – diastolic BP.

Results

Patients with a history of heart failure and stroke (n = 42) were excluded leaving 382 participants for final analysis. When categorized into tertiles of PP, participants within the highest PP tertile had significantly slower gait speed than those within the lowest PP tertile (p<0.05). Following stepwise multiple regression, PP was significantly and inversely associated with 400-meter gait speed (p<0.05). Other significant predictors of gait speed included: handgrip strength, body weight, age and history of diabetes mellitus (p<0.05). Mean arterial pressure, systolic BP and diastolic BP were not predictors of gait speed.

Conclusions

Pulse pressure is associated long-distance gait speed in community-dwelling older adults. Vascular senescence and altered ventricular-vascular coupling may be associated with the deterioration of mobility and physical function in older adults.     

Platelet function in stored heparinised autologous blood is not superior to in patient platelet function during routine cardiopulmonary bypass

Background

In cardiac surgery, cardiopulmonary bypass (CPB) and unfractionated heparin have negative effects on blood platelet function. In acute normovolemic haemodilution autologous unfractionated heparinised blood is stored ex-vivo and retransfused at the end of the procedure to reduce (allogeneic) transfusion requirements. In this observational study we assessed whether platelet function is better preserved in ex vivo stored autologous blood compared to platelet function in the patient during CPB.

Methodology/Principal Finding

We measured platelet aggregation responses pre-CPB, 5 min after the start of CPB, at the end of CPB, and after unfractionated heparin reversal, using multiple electrode aggregometry (Multiplate®) with adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP) and ristocetin activated test cells. We compared blood samples taken from the patient with samples taken from 100 ml ex-vivo stored blood, which we took to mimick blood storage during normovolemic haemodilution. Platelet function declined both in ex-vivo stored blood as well as in blood taken from the patient. At the end of CPB there were no differences in platelet aggregation responses between samples from the ex vivo stored blood and the patient.

Conclusion/Significance

Ex vivo preservation of autologous blood in unfractionated heparin does not seem to be profitable to preserve platelet function.