Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis

Previous studies have shown that colony stimulating factor-1 (CSF-1) deficiency dramatically reduced atherogenesis in mice. In this report we investigate this mechanism and explore a therapeutic avenue based on inhibition of CSF-1 signaling. Lesions from macrophage colony stimulating factor-1 (Csf1)^+/− mice showed increased numbers of apoptotic macrophages, decreased overall macrophage content, and inflammation. In vitro studies indicated that CSF-1 is chemotactic for monocytes. Bone marrow transplantation studies suggested that vascular cell-derived, rather than macrophage-derived, CSF-1 is responsible for the effect on atherosclerosis. Consistent with previous studies, CSF-1 affected lesion development in a dose-dependent manner, suggesting that pharmacological inhibition of CSF-1 might achieve similar results. Indeed, we observed that treatment of hyperlipidemic mice with a CSF-1 receptor kinase inhibitor inhibited plaque progression. This observation was accompanied by a reduction in the expression of adhesion factors (ICAM-1), macrophage markers (F4/80), inflammatory cytokines (Il-6, Il-1β), and macrophage matrix degradation enzymes (MMP-9). We conclude that the M-CSF pathway contributes to monocyte recruitment and macrophage survival and that this pathway is a potential target for therapeutic intervention.     

Variations in Kinematics during Clinical Gait Analysis in Stroke Patients

In addition to changes in spatio-temporal and kinematic parameters, patients with stroke exhibit fear of falling as well as fatigability during gait. These changes could compromise interpretation of data from gait analysis. The aim of this study was to determine if the gait of hemiplegic patients changes significantly over successive gait trials. Forty two stroke patients and twenty healthy subjects performed 9 gait trials during a gait analysis session. The mean and variability of spatio-temporal and kinematic joint parameters were analyzed during 3 groups of consecutive gait trials (1–3, 4–6 and 7–9). Principal component analysis was used to reduce the number of variables from the joint kinematic waveforms and to identify the parts of the gait cycle which changed during the gait analysis session. The results showed that i) spontaneous gait velocity and the other spatio-temporal parameters significantly increased, and ii) gait variability decreased, over the last 6 gait trials compared to the first 3, for hemiplegic patients but not healthy subjects. Principal component analysis revealed changes in the sagittal waveforms of the hip, knee and ankle for hemiplegic patients after the first 3 gait trials. These results suggest that at the beginning of the gait analysis session, stroke patients exhibited phase of adaptation,characterized by a “cautious gait” but no fatigue was observed.     

Effects of Quadriceps Muscle Fatigue on Stiff-Knee Gait in Patients with Hemiparesis

The relationship between neuromuscular fatigue and locomotion has never been investigated in hemiparetic patients despite the fact that, in the clinical context, patients report to be more spastic or stiffer after walking a long distance or after a rehabilitation session. The aim of this study was to evaluate the effects of quadriceps muscle fatigue on the biomechanical gait parameters of patients with a stiff-knee gait (SKG). Thirteen patients and eleven healthy controls performed one gait analysis before a protocol of isokinetic quadriceps fatigue and two after (immediately after and after 10 minutes of rest). Spatiotemporal parameters, sagittal knee and hip kinematics, rectus femoris (RF) and vastus lateralis (VL) kinematics and electromyographic (EMG) activity were analyzed. The results showed that quadriceps muscle weakness, produced by repetitive concentric contractions of the knee extensors, induced an improvement of spatiotemporal parameters for patients and healthy subjects. For the patient group, the increase in gait velocity and step length was associated with i) an increase of sagittal hip and knee flexion during the swing phase, ii) an increase of the maximal normalized length of the RF and VL and of the maximal VL lengthening velocity during the pre-swing and swing phases, and iii) a decrease in EMG activity of the RF muscle during the initial pre-swing phase and during the latter 2/3 of the initial swing phase. These results suggest that quadriceps fatigue did not alter the gait of patients with hemiparesis walking with a SKG and that neuromuscular fatigue may play the same functional role as an anti-spastic treatment such as botulinum toxin-A injection. Strength training of knee extensors, although commonly performed in rehabilitation, does not seem to be a priority to improve gait of these patients.     

Ascending curbs of progressively higher height increases forward trunk flexion along with upper extremity mechanical and muscular demands in manual wheelchair users with a spinal cord injury

High upper extremity (U/E) demands are required when manual wheelchair users (MWUs) with spinal cord injury (SCI) ascend curbs; this may contribute to the risk of developing U/E musculoskeletal impairments. The aim of this study was to compare movement strategies (kinematics), mechanical loads (kinetics) and muscular demand (EMG) at the non-dominant U/E among 15 MWUs with SCI when ascending curbs of 4 cm (3 trials), 8 cm (3 trials) and 12 cm high (3 trials) from a starting line set 3 m before the curb. Biomechanical data was collected during three trials for each height. The curb ascent task was divided into three adjustment phases: caster pop, rear-wheel ascent and post-ascent. The greatest effort was generated by the shoulder flexors and internal rotators as well as the elbow flexors. A significant difference (p < 0.0167) between the curb heights was found for most outcome measures studied: movement excursion, net joint moments and muscular utilization ratio (MUR) of the main muscles increased with the higher curb heights, mainly around the shoulder joint. These results provide insight that aside from adhering to a highly structured training method for wheelchair curb ascent, rehabilitation professionals need to propose task-specific strength training programs based on the demands documented in this study and continue to advocate for physically accessible environments.     

Changes in electromyographic activity after botulinum toxin injection of the rectus femoris in patients with hemiparesis walking with a stiff-knee gait

PurposeThis study was designed to evaluate the effects of botulinum toxin type-A (BoNTA) injection of the rectus femoris (RF) muscle on the electromyographic activity of the knee flexor and extensor and on knee and hip kinematics during gait in patients with hemiparesis exhibiting a stiff-knee gait.MethodTwo gait analyses were performed on fourteen patients: before and four weeks after BoNTA injection. Spatiotemporal, kinematic and electromyographic parameters were quantified for the paretic limb.ResultsBoNTA treatment improved gait velocity, stride length and cadence with an increase of knee angular velocity at toe-off and maximal knee flexion in the swing phase. Amplitude and activation time of the RF and co-activation duration between the RF and biceps femoris were significantly decreased. The instantaneous mean frequency of RF was predominantly lower in the pre-swing phase.ConclusionsThe results clearly show that BoNTA modified the EMG amplitude and frequency of the injected muscle (RF) but not of the synergist and antagonist muscles. The reduction in RF activation frequency could be related to increased activity of slow fibers. The frequency analysis of EMG signals during gait appears to be a relevant method for the evaluation of the effects of BoNTA in the injected muscle.     

TLR/MyD88 and liver X receptor alpha signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis

Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE)(-/-) mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor alpha (LXRalpha) signaling pathways. We infected ApoE(-/-) mice and ApoE(-/-) mice that also lacked TLR2, TLR4, MyD88, or LXRalpha intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-alpha. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE(-/-) mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE(-/-) mice was further enhanced in ApoE(-/-)LXRalpha(-/-) double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-alpha. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRalpha appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.     

Antidepressant,anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist

Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. In addition, after mapping the binding sites for [(3)H]SNAP-7941 in rat brain, we evaluated its effects in a series of behavioral models. SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in three animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea pig maternal-separation vocalization tests. Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety.