Impact of Spinal Manipulation on Lower Extremity Motor Control in Lumbar Spinal Stenosis Patients: A Small-Scale Assessor-Blind Randomized Clinical Trial.

OBJECTIVE: The purpose of this study was to quantify the impact of a single lumbar spinal manipulation (SM) intervention on the leg movement performance of degenerative lumbar spinal stenosis (LSS) patients in a small-scale registered randomized clinical trial. METHODS: Participants with LSS (n = 14) were tested at baseline for pain, lumbar range of motion, and behavioral or kinematic motor performance (using an established Fitts' Law foot-pointing task), then underwent covariate adaptive randomization to receive SM or no intervention. Postintervention all dependent measures were repeated. Experimenters were blinded to patient group allocation. University ethics board approval was attained. RESULTS: For the primary outcome movement time, there was no significant difference between groups. As predicted by Fitts' Law, all participants had longer movement times as task difficulty increased. Secondary kinematic outcomes yielded no significant between-group differences. Consistent with Fitts' Law, kinematic measures changed significantly with task difficulty. Pairwise comparisons revealed the kinematic variables were more adversely affected by greater movement amplitudes than target size changes. No exploratory differences in pain or lumbar range of motion were observed. CONCLUSION: Changes in motor performance were not observed in this chronic pain population after a single SM intervention compared with a control group. Given the sample size, the study may have been underpowered to detect meaningful differences. Fitts' Law was observed for the lower extremity-pointing task for an LSS population and may provide an objective measure of motor performance.

MMP-2 mediates angiotensin II-induced hypertension under the transcriptional control of MMP-7 and TACE.

Development of cardiovascular disease induced by excessive Gq protein-coupled receptor agonist stimulation depends on signaling networks involving multiple matrix metalloproteinases (MMPs) and metalloproteinase disintegrins (ADAMs). Here, we hypothesized that MMP-2, being a major gelatinase in cardiac and vascular tissue, was likely to play a key role in cardiovascular homeostasis. We targeted MMP-2 using complementary and overlapping approaches involving pharmacological inhibition and RNA interference in mice treated with angiotensin II (1.4 mg/kg per day) for 12 days. We studied the development of hypertension (by tail cuff plethysmography), cardiac hypertrophy (by M-mode echocardiography, cardiomyocyte cross-sectional area, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis of hypertrophy marker genes), and fibrosis (by picrosirius red collagen staining and qRT-PCR analysis of fibrosis marker genes) in mice receiving angiotensin II. We found that angiotensin II infusion upregulated MMP-2 concurrent with the development of hypertension, hypertrophy, and fibrosis. This upregulation of MMP-2 depended on MMP-7 and TACE (tumor necrosis factor-α convertase, ADAM-17). RNA interference targeting MMP-7 and TACE attenuated the angiotensin II-induced upregulation of MMP-2 and prevented the development of hypertension, as well as development of cardiac hypertrophy and fibrosis. In contrast, pharmacological inhibition and RNA interference of MMP-2 attenuated angiotensin II-induced hypertension, without influencing development of cardiac hypertrophy or fibrosis. Downstream of MMP-7 and TACE, MMP-2 mediated angiotensin II-induced hypertension, but did not mediate cardiac hypertrophy or fibrosis. This suggests a functional specialization of MMP-2 in agonist-induced cardiovascular disease development that has potential implications for the design of metalloproteinase-based therapeutic strategies.

Tumor necrosis factor-alpha-converting enzyme is a key regulator of agonist-induced cardiac hypertrophy and fibrosis.

Cardiac remodeling is associated with hypertrophy and fibrosis processes, which may depend on the activity of matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinases" (ADAMs). We investigated whether ADAM-17 (tumor necrosis factor-alpha-converting enzyme [TACE]) plays a role in agonist-induced cardiac remodeling and the relationships established among TACE, MMP-2, and ADAM-12. We targeted TACE in rodent models of spontaneous and agonist-induced hypertension using RNA interference combined with quantitative RT-PCR, activity determinations, and functional studies. Treatment of spontaneously hypertensive rats with previously validated TACE small-interfering RNA for 28 days resulted in systemic knockdown of TACE expression. TACE knockdown effectively stopped the development of cardiac hypertrophy. Mice receiving angiotensin II (1.4 mg/kg per day for 12 days) exhibited cardiac hypertrophy, as well as fibrosis, which was associated with elevated myocardial expression of molecular markers of hypertrophy (alpha-skeletal actin, beta-myosin heavy chain, and brain natriuretic peptide) and fibrosis (collagen types I and III and fibronectin), as well as MMP-2 and ADAM-12. Treatment with TACE small-interfering RNA (but not with PBS or luciferase small-interfering RNA) inhibited TACE expression, thus preventing angiotensin II-induced cardiac hypertrophy and fibrosis. Moreover, knockdown of TACE inhibited angiotensin II-induced overexpression of markers of myocardial hypertrophy and fibrosis, as well as ADAM-12 and MMP-2. These findings provide the first in vivo evidence that agonist-induced cardiac hypertrophy and fibrosis processes are signaled through TACE, which acts through novel pathways involving transcriptional regulation of ADAM-12 and MMP-2. Targeting TACE has potential therapeutic importance for modulating agonist-induced cardiac remodeling.

Matrix metalloproteinase-7 and ADAM-12 (a disintegrin and metalloproteinase-12) define a signaling axis in agonist-induced hypertension and cardiac hypertrophy.

BACKGROUND: Excessive stimulation of Gq protein-coupled receptors by cognate vasoconstrictor agonists induces a variety of cardiovascular processes, including hypertension and hypertrophy. Here, we report that matrix metalloproteinase-7 (MMP-7) and a disintegrin and metalloproteinase-12 (ADAM-12) form a novel signaling axis in these processes. METHODS AND RESULTS: In functional studies, we targeted MMP-7 in rodent models of acute, long-term, and spontaneous hypertension by 3 complementary approaches: (1) Pharmacological inhibition of activity, (2) expression knockdown (by antisense oligodeoxynucleotides and RNA interference), and (3) gene knockout. We observed that induction of acute hypertension by vasoconstrictors (ie, catecholamines, angiotensin II, and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester) required the posttranscriptional activation of vascular MMP-7. In spontaneously hypertensive rats, knockdown of MMP-7 (by RNA interference) resulted in attenuation of hypertension and stopped development of cardiac hypertrophy. Quantitative reverse-transcription polymerase chain reaction studies in mouse models of MMP-7 knockdown (by RNA interference) and gene knockout revealed that MMP-7 controlled the transcription of ADAM-12, the major metalloproteinase implicated in cardiac hypertrophy. In mice with angiotensin II-induced hypertension and cardiac hypertrophy, myocardial ADAM-12 and downstream hypertrophy marker genes were overexpressed. Knockdown of MMP-7 attenuated hypertension, inhibited ADAM-12 overexpression, and prevented cardiac hypertrophy. CONCLUSIONS: Agonist signaling of both hypertension and hypertrophy depends on posttranscriptional and transcriptional mechanisms that involve MMP-7, which is transcriptionally connected with ADAM-12. Approaches targeting this novel MMP-7/ADAM-12 signaling axis could have generic therapeutic potential in hypertensive disorders caused by multiple or unknown agonists.

Chiropractic management of tendinopathy: a literature synthesis.

OBJECTIVE: Chronic tendon pathology is a soft tissue condition commonly seen in chiropractic practice. Tendonitis, tendinosis, and tendinopathy are terms used to describe this clinical entity. The purpose of this article is to review interventions commonly used by doctors of chiropractic when treating tendinopathy. METHODS: The Scientific Commission of the Council on Chiropractic Guidelines and Practice Parameters (CCGPP) was charged with developing literature syntheses, organized by anatomical region, to evaluate and report on the evidence base for chiropractic care. This article is the outcome of this charge. As part of the CCGPP process, preliminary drafts of these articles were posted on the CCGPP Web site www.ccgpp.org (2006-8) to allow for an open process and the broadest possible mechanism for stakeholder input. A literature search was performed using the PubMed; Cumulative Index to Nursing and Allied Health Literature; Index to Chiropractic Literature; Manual, Alternative, and Natural Therapy Index System; National Guidelines Clearinghouse; Database of Abstracts of Reviews of Effects; and Turning Research Into Practice databases. The inclusion criteria were manual therapies, spinal manipulation, mobilization, tendonitis, tendinopathy, tendinosis, cryotherapy, bracing, orthotics, massage, friction massage, transverse friction massage, electrical stimulation, acupuncture, exercise, eccentric exercise, laser, and therapeutic ultrasound. RESULTS: There is evidence that ultrasound therapy provides clinically important improvement in the treatment of calcific tendonitis. There is limited evidence of the benefit of manipulation and mobilization in the treatment of tendinopathy. Limited evidence exists to support the use of supervised exercise, eccentric exercise, friction massage, acupuncture, laser therapy, use of bracing, orthotics, and cryotherapy in the treatment of tendinopathy. CONCLUSION: Chiropractors often provide a number of conservative interventions commonly used to treat tendinopathy.