Differing Characteristics of Human-Shaped Visual Stimuli Affect Clinicians' Dosage of a Spinal Manipulative Thrust on a Low-Fidelity Model: A Cross-Sectional Study.

OBJECTIVE: The purpose of this study was to determine whether chiropractic clinicians modulate spinal manipulation (SM) thrust characteristics based on visual perception of simulated human silhouette attributes. METHODS: We performed a cross-sectional within-participant design with 8 experienced chiropractors. During each trial, participants observed a human-shaped life-sized silhouette of a mock patient and delivered an SM thrust on a low-fidelity thoracic spine model based on their visual perception. Silhouettes varied on the following 3 factors: apparent sex (male or female silhouette), height (short, average, tall), and body mass index (BMI) (underweight, healthy, obese). Each combination was presented 6 times for a total of 108 trials in random order. Outcome measures included peak thrust force, thrust duration, peak preload force, peak acceleration, time to peak acceleration, and rate of force application. A 3-way repeated measures analysis of variance model was used to for each variable, followed by Tukey's honestly significant difference on significant interactions. RESULTS: Peak thrust force was reduced when apparent sex of the presented silhouette was female (F1,7 = 5.70, P = .048). Thrust duration was largely invariant, except that a BMI by height interaction revealed a longer duration occurred for healthy tall participants than healthy short participants (F4,28 = 4.34, P = .007). Compared to an image depicting obese BMI, an image appearing underweight lead to reduced peak acceleration (F2,5 = 6.756, P = .009). Clinician time to peak acceleration was reduced in short compared to tall silhouettes (t7 = 2.20, P = .032). CONCLUSION: Visual perception of simulated human silhouette attributes, including apparent sex, height, and BMI, influenced SM dose characteristics through both kinetic and kinematic measures. The results suggest that visual information from mock patients affects the decision-making of chiropractic clinicians delivering SM thrusts.

Tactile Perception of Pressure and Volitional Thrust Intensity Modulate Spinal Manipulation Dose Characteristics.

OBJECTIVE: The purpose of this study was to examine clinicians' ability to modulate spinal manipulation (SM) thrust characteristics based on their tactile perception of pressure and volitional intensity. METHODS: In a cross-sectional, within-participants design, 13 doctors of chiropractic delivered SM thrusts of perceived least, appropriate, or greatest intensity of their perceived safe output level for an SM thrust on low-fidelity thoracic spine models of 4 different pressure levels. The participants performed SM over the course of 96 trials in a randomized order on combinations of thrust intensity and pressure. Dependent variables included normalized preload force, thrust force, thrust duration, peak acceleration, time to peak acceleration, and displacement. For all dependent measures, 2-factor within-participants analysis of variance models with repeated measures on both factors were performed. RESULTS: Preload force increased with intensity (F2,24 = 9.72; P < .001) and model pressure (F3,36 = 4.27; P = .011). Participants modulated thrust force and displacement as each also increased with intensity escalation (F2,24 = 22.53, P < .001; F2,18 = 45.20, P < .001). The highest accelerations were observed during the greatest intensity. Increased thrust force was delivered at higher model pressures (F3,36 = 6.43; P < .001). A significant interaction demonstrated that as volitional thrust intensity increased, greater displacement was attained, particularly on low pressure models (F6,54 = 11.06; P < .001). Thrust duration and time to peak acceleration yielded no significant differences. CONCLUSION: Spinal manipulation thrust dosage was modulated by the chiropractors' tactile perception of pressure and volitional intensity.

The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis.

Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection.

Lower cortisol levels in children with asthma exposed to recurrent maternal distress from birth.

BACKGROUND: Existing evidence supports associations between exposure to maternal distress and the development of childhood asthma, between exposure to maternal distress and an increased cortisol response in children, and between childhood asthma and an attenuated cortisol response. OBJECTIVE: To investigate the association between children's cortisol levels and the combined predictors of exposure to maternal distress and childhood asthma. METHODS: Serum cortisol levels were examined at age 7 to 10 years in relation to asthma status and exposure to maternal distress in a representative sample of children (n = 503) born in 1995. Data from health care and prescription databases were linked with additional data collected in this longitudinal study. Maternal distress was defined as a physician diagnosis of a depressive or anxiety disorder or a prescription history of related medications as reported in the mothers' health care records. Children's asthma status was determined via examination by 2 pediatric allergists. RESULTS: A multiple linear regression analysis revealed that exposure to maternal distress restricted to the first year of life predicted elevated cortisol levels in children, regardless of asthma status (>40% increase). A significant interaction was discovered in the group of children exposed to maternal distress extending beyond the postnatal period such that no asthma predicted a 25.9% increase in cortisol and a diagnosis of asthma predicted a 5.2% decrease in cortisol. Cortisol levels were further lowered in atopic and bronchial hyperresponsive asthma. CONCLUSION: Among children exposed to recurrent maternal distress, an elevation in cortisol levels occurs in response to an acute stressor when there is no accompanying diagnosis of asthma, whereas, in comparison, children with asthma tend to exhibit lower cortisol levels.

Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma.

RATIONALE: Evidence is emerging that exposure to maternal distress in early life plays a causal role in the development of childhood asthma. OBJECTIVES: Because much of the data are from high-risk cohorts, we undertook a birth cohort study in a complete population of children to test this association. METHODS: Using Manitoba, Canada's, health care and prescription databases, this longitudinal study assessed the association between maternal distress during the first year of life and onward, and asthma at age 7 in a 1995 birth cohort of 13,907 children. MEASUREMENTS AND MAIN RESULTS: Maternal distress was defined on the basis of health care or prescription medication use for depression or anxiety. Asthma status was derived from health care and prescription records for asthma, using a definition validated by comparison to pediatric allergist diagnosis. Multiple logistic regression was used to determine the likelihood of asthma (odds ratio [OR], 95% confidence interval [95% CI]). Independent of well-known asthma risk factors, our population-based study of a non-high-risk cohort demonstrated an increased risk of childhood asthma (OR, 1.25; 95% CI, 1.01-1.55) among children exposed to continued maternal distress from birth until age 7. Exposure to maternal depression and anxiety limited to the first year of life did not have a demonstrable association with subsequent asthma. Of interest, we observed that the risk of asthma associated with continued maternal distress was increased in children living in high- versus low-income households (OR, 1.44; 95% CI, 1.12-1.85). CONCLUSIONS: Maternal distress in early life plays a role in the development of childhood asthma, especially if it continues beyond the postpartum period.

Diagnostic Accuracy of the Slump Test for Identifying Neuropathic Pain in the Lower Limb.

STUDY DESIGN: Diagnostic accuracy study with nonconsecutive enrollment. OBJECTIVES: To assess the diagnostic accuracy of the slump test for neuropathic pain (NeP) in those with low to moderate levels of chronic low back pain (LBP), and to determine whether accuracy of the slump test improves by adding anatomical or qualitative pain descriptors. BACKGROUND: Neuropathic pain has been linked with poor outcomes, likely due to inadequate diagnosis, which precludes treatment specific for NeP. Current diagnostic approaches are time consuming or lack accuracy. METHODS: A convenience sample of 21 individuals with LBP, with or without radiating leg pain, was recruited. A standardized neurosensory examination was used to determine the reference diagnosis for NeP. Afterward, the slump test was administered to all participants. Reports of pain location and quality produced during the slump test were recorded. RESULTS: The neurosensory examination designated 11 of the 21 participants with LBP/sciatica as having NeP. The slump test displayed high sensitivity (0.91), moderate specificity (0.70), a positive likelihood ratio of 3.03, and a negative likelihood ratio of 0.13. Adding the criterion of pain below the knee significantly increased specificity to 1.00 (positive likelihood ratio = 11.9). Pain-quality descriptors did not improve diagnostic accuracy. CONCLUSION: The slump test was highly sensitive in identifying NeP within the study sample. Adding a pain-location criterion improved specificity. Combining the diagnostic outcomes was very effective in identifying all those without NeP and half of those with NeP. Limitations arising from the small and narrow spectrum of participants with LBP/sciatica sampled within the study prevent application of the findings to a wider population. LEVEL OF EVIDENCE: Diagnosis, level 4-.

Acceleration of clinician hand movements during spinal manipulative therapy.

This study used an observational design to examine the kinematics of spinal manipulative therapy (SMT) by determining the acceleration characteristics of the manipulative input at the cervical, thoracic, and lumbar spinal regions. Studies of SMT have been restricted to measuring the forces that result from the manipulative input. Several studies have indicated the rate of force development is a key parameter of clinically delivered SMT. Despite this, the movement strategies employed during SMT, including acceleration, have not been directly measured. Participants (n = 29) were recruited from a private practice chiropractic clinic. A wireless accelerometer attached to the clinician's hand was used to characterize the thrust phase of the SMT treatments. Significant differences were found across each spinal region for acceleration amplitude parameters (p < 0.0001). Post-hoc analysis indicated that amplitudes significantly increased in order from thoracic to cervical to lumbar regions (p < 0.0001). Spinal level was also a significant factor in determining the temporal parameters of hand acceleration during SMT (p < 0.0005). This study provides a description of the acceleration properties of clinically delivered SMT. Consistent with that reported for SMT forces, acceleration amplitudes varied significantly across spinal regions with relatively little differences in acceleration latencies. Notably, acceleration amplitudes and latencies were not associated with each other within spinal regions. These findings indicate that changes in acceleration amplitude, rather than latency, are used to tailor SMT to individuals.

Neurochemical excitation of thoracic propriospinal neurons improves hindlimb stepping in adult rats with spinal cord lesions.

Using an in vitro neonatal rat brainstem-spinal cord preparation, we previously showed that cervicothoracic propriospinal neurons contribute to descending transmission of the bulbospinal locomotor command signal, and neurochemical excitation of these neurons facilitates signal propagation. The present study examined the relevance of these observations to adult rats in vivo. The first aim was to determine the extent to which rats are able to spontaneously recover hindlimb locomotor function in the presence of staggered contralateral hemisections (left T2-4 and right T9-11) designed to abolish all long direct bulbospinal projections. The second aim was to determine whether neurochemical excitation of thoracic propriospinal neurons in such animals facilitates hindlimb stepping. In the absence of intrathecal drug injection, all animals (n=24) displayed some degree of hindlimb recovery ranging from weak ankle movements to brief periods of unsupported hindlimb stepping on the treadmill. The effect of boluses of neurochemicals delivered via an intrathecal catheter (tip placed midway between the rostral and caudal thoracic hemisections) was examined at post-lesion weeks 3, 6 and 9. Quipazine was particularly effective facilitating hindlimb stepping. Subsequent complete transection above the rostral (n=3) or caudal (n=2) hemisections at week 9 had no consistent effect on drug-free locomotor performance, but the facilitatory effect of drug injection decreased in 4/5 animals. Two animals underwent complete transection at T3 as the first and only surgery and implantation of two intrathecal catheters targeted to the mid-thoracic and lumbar regions, respectively. A similar facilitatory effect on stepping was observed in response to drugs administered via either catheter. The results indicate that partial spontaneous recovery of stepping occurs in adult rats after abolishing all long direct bulbospinal connections, in contrast to previous studies suggesting that hindlimb stepping after dual hemisections either does not occur or is observed only if the second hemisection surgery is delayed relative to the first. The results support the hypothesis that artificial modulation of propriospinal neuron excitability may facilitate recovery of motor function after spinal cord injury. However, whether this facilitation is due to enhanced transmission of a descending locomotor signal or is the result of excitation of thoracolumbar circuits independent of supraspinal influence, requires further study.

Increased GAD67 mRNA levels are correlated with in vivo GABA synthesis in the MPTP-treated catecholamine-depleted goldfish brain.

The role of catecholamine neuronal input on GABAergic activity in the hypothalamus, telencephalon, optic tectum, and cerebellum was investigated in early recrudescent female goldfish (Carassius auratus). A new quantitative technique was developed and validated, permitting concomitant quantification and correlational analysis of glutamic acid decarboxylase 65 (GAD65), GAD67, and GAD3 mRNA levels and in vivo GABA synthesis. Catecholamine depletion was achieved by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 50 microg/g body weight) and dopamine (DA) depletion verified by HPLC. Endogenous GABA levels were increased by intraperitoneal administration of gamma-vinyl GABA (GVG; 300 microg/g body weight), an inhibitor of the GABA catabolic enzyme GABA transaminase. Treatment with MPTP resulted in a greater than twofold increase in GABA synthesis rate in the optic tectum and telencephalon. The increase in GABA synthesis rate was highly correlated with an increase in GAD67, but not GAD65 or GAD3 mRNA levels. These results suggest that catecholaminergic input exerts inhibitory effects on GABA synthesis rates through the modulation of GAD67 in the optic tectum and telencephalon. Together with previously published observations in rodents and primates, it is suggested that catecholaminergic control of GABA synthesis must have evolved more than 200 million years ago, before the emergence of the teleost fishes.

A novel pulsatile, laminar flow bioreactor for the development of tissue-engineered vascular structures.

Exposure of vascular cell-seeded, tubular, biodegradable polymers to pulsatile flow conditions has been proposed as a method to develop tissue-engineered blood vessels by "maturing" structural integrity, and increasing collagen content, suture retention, burst pressure, and tissue formation. These in vitro tissue-engineered arteries demonstrate contractile responses to pharmacologic agents and express markers of vascular differentiation. Current methods to induce pulsatile flow in a bioreactor system are limited by the creation of nonphysiologic pressure waveforms and noncompliant reservoirs to house the tissue-engineered vascular constructs. We have developed a novel method for the in vitro development of tubular vascular structures by using a mechanical ventilator to induce pulsatile, laminar flow into a fluid column, resulting in pressurized waveforms similar to mammalian physiology. The vascular constructs are housed in semicompliant tubing to facilitate an additional variable of circumferential stretch as a potential signaling mechanism. This approach more closely approximates mammalian physiology and we hypothesize that it will facilitate mechanical signaling necessary for the development of tissue-engineered vessels for clinical applications.

The effects of sildenafil on the cardiovascular response in men with spinal cord injury at or above the sixth thoracic level.

BACKGROUND: Sildenafil is efficacious for erectile dysfunction in men with spinal cord injury (SCI), but can induce hypotension in neurologically intact people. Those with SCI at or above the sixth thoracic level (T6) often have pre-existing hypotension, yet the cardiovascular response to sildenafil has not been studied in this group. OBJECTIVE: To evaluate the effect of sildenafil on the cardiovascular response in men with complete SCI at or above T6. METHODS: This was a randomized, double-blind, placebo-controlled, cross-over study. Twenty-three SCI participants were each randomly given placebo; sildenafil, 50 mg; and sildenafil, 100 mg; separated by at least 1 week. The following were measured before administration, and hourly for 4 hours afterward: (a) blood pressure (BP) and heart rate (HR), both supine and sitting; and (b) perceived dizziness on a visual analog scale upon sitting. RESULTS: Analysis was done using a 4-way repeated-measures analysis of variance. No significant changes occurred with placebo. Sildenafil caused the following changes. Systolic BP changed little in thoracic spinal cord-injured (TSCI) participants, but decreased significantly (P < 0.005) in cervical spinal cord-injured (CSCI) participants. Diastolic BP decreased in all participants (P < 0.005). HR increased in the TSCI participants for 1 hour (P < 0.05), but was not altered in the CSCI participants. Dizziness increased in the TSCI participants after administration of 100 mg (P < 0.05) and in the CSCI participants after administration of 50 mg (P < 0.05). There were no adverse events or outcomes. CONCLUSION: Sildenafil induces significant hypotension in people with cervical-level injuries--more so than in thoracic-level injuries--and can cause dizziness in both populations. It should be prescribed with caution and informed consent from the patient.

Elevated expression of fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) in the dorsal root ganglia and spinal cord in experimental autoimmune encephalomyelitis: implications in multiple sclerosis-induced neuropathic pain.

Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG/SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS.

Neuropeptide specificity of prostaglandin E2-induced activation of splenic and renal sympathetic nerves in the rat.

Sympathetic activation occurs rapidly following intracerebroventricular (icv) injection of prostaglandin E2(PGE2). This study examined whether neuropeptides mediate PGE2-induced sympathetic nerve activation in urethane/chloralose-anesthetized Sprague-Dawley rats. Animals were pretreated (20.0 microg, icv) with the following receptor antagonists; CRF ([D-Phe12,Nle21,38,Calpha-MeLeu37]CRF12-41), AVP-V1 (Des-Gly-[Phaa1, D-Tyr(Et)2,Lys6,Arg8]-vasopressin), or OT (OT+V1, [d(CH2)5,Tyr(Me)2,Orn8]-vasotocin) followed 20 min later by PGE2 (2.0 microg, icv). Pretreatment with the CRF antagonist attenuated the increase in renal nerve activity induced by PGE2 when measured 10 and 30 min post-injection. PGE2-induced renal nerve activity was also inhibited at both time points by the AVP antagonist and, to a similar extent, the OT antagonist. The AVP antagonist did not effect splenic nerve responses to PGE2 whereas the CRF antagonist produced an incomplete and transient reduction in PGE2-induced activation of the splenic nerve. However, the OT antagonist completely blocked the activation of the splenic nerve after central injection of PGE2. ICV injections of AVP and OT produced immediate changes in splenic and renal nerve activity whereas CRF failed to alter the activity of either nerve in anesthetized or conscious animals. Thus, PGE2 acts through neuropeptide-specific pathways to initiate sympathetic outflow and OT is a specific component of the sympathetic pathway innervating the spleen.

Stress-induced suppression of in vivo splenic cytokine production in the rat by neural and hormonal mechanisms.

The mechanisms mediating the effects of stress on immune function have yet to be fully described. In vitro studies have demonstrated a role for both the sympathetic nervous system (SNS) and the hypothalamic pituitary adrenal axis (HPAA) in regulating immune responses following exposure to various stressors. The purpose of the present set of experiments was to determine the in vivo contribution of the HPAA and SNS in regulating the effects of stress on lipopolysaccharide (LPS) induced splenic cytokine production. For this, rats with combinations of sham surgeries, splenic nerve cuts (SNC), and adrenalectomies (ADX) were exposed to 15 min of 1.6 mA intermittent footshock immediately following the intravenous (i.v.) injection of 0.1 microg of LPS. Although footshock was immunosuppressive to most indices of cytokine production, neither SNC nor ADX alone blocked the effects of stress on splenic immune function. However the combination of these two manipulations significantly abrogated the immunosuppressive effects of stress on cytokine production. Adrenal demedullation of animals with a SNC demonstrated that the SNS, not the HPAA, was primarily responsible for the immunosuppressive effects of stress.

Contribution of the adrenal glands and splenic nerve to LPS-induced splenic cytokine production in the rat.

Both the hypothalamic pituitary adrenal axis (HPAA) and the sympathetic nervous system (SNS) can inhibit immune function and are regarded as the primary efferent pathways for neural-immune interactions. To determine if this relationship is maintained in vivo in response to an inflammatory stimulus, rats were injected intravenously (iv) with various doses of lipopolysaccharide (LPS) and splenic cytokine mRNA and protein levels were measured at several dose and time intervals post-injection. The spleen was chosen as the target organ because both the neural and hormonal inputs to the spleen can be selectively removed by splenic nerve cut (SNC) and adrenalectomy (ADX), respectively. Data from our dose response studies established that maximum levels of splenic cytokines were induced in response to relatively low doses of LPS. Minimal changes in LPS-induced splenic cytokine levels were observed in response to ADX, SNC, or a combination of the two procedures across several doses of LPS. These results suggest that there are aspects of immune regulation that are functionally removed from these central modulatory systems and that the counter-regulatory responses induced by LPS have minimal impact on the concurrent induction of cytokines by this inflammatory stimulus. The conceptual model of neural-immune regulation as an inhibitory feedback system, at least with regards to the early activational effects induced by an inflammatory stimulus, was not supported by these studies.