An integrated analysis of five double-blind, randomized controlled trials evaluating the safety and efficacy of a hyaluronan product for intra-articular injection in osteoarthritis of the kneel

Objective: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials. Method. Trials were similar in design, patient population and outcome measures - all included the Lequesne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized. Results: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received. placebo saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequesne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequesne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95% CI: -0.56 to -0.79), effect size 0.20. Additional modeling approaches confirmed robustness of the analyses. Conclusions: This integrated analysis demonstrates that multiple design factors influence the results of RCTs assessing efficacy of intra-articular (IA) therapies, and that integrated analyses based on primary data differ from meta-analyses using transformed data. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Analysis of the thermal stress behaviour of functionally graded hollow circular cylinders

This paper presents an analysis of the thermomechanical behavior of hollow circular cylinders of functionally graded material (FGM). The solutions are obtained by a novel limiting process that employs the solutions of homogeneous hollow circular cylinders, with no recourse to the basic theory or the equations of non-homogeneous thermoclasticity. Several numerical cases are studied, and conclusions are drawn regarding the general properties of thermal stresses in the FGM cylinder. We conclude that thermal stresses necessarily occur in the FGM cylinder, except in the trivial case of zero temperature. While heat resistance may be improved by sagaciously designing the material composition, careful attention must be paid to the fact that thermal stresses in the FGM cylinder are governed by more factors than are its homogeneous counterparts. The results that are presented here will serve as benchmarks for future related work. (C) 2003 Elsevier Science Ltd. All rights reserved.

The role of morphine-6-glucuronide (M6G) in pain control

Morphine-6beta-D-glucuronide (M6G) is an analgesically active metabolite of morphine, accounting for approximate to10% of the morphine dose when administered by systemic routes to humans. Although M6G is more hydrophilic than morphine, it crosses the blood-brain barrier, albeit relatively slowly. For this reason, it is generally thought that, after chronic dosing, M6G contributes significantly to the analgesic effects of systemically administered morphine. Owing to its polar nature, M6G is cleared from the systemic circulation primarily via renal elimination. As M6G accumulates in patients with renal impairment, there is an increased risk of M6G-induced respiratory depression in renal failure patients who are being dosed chronically with systemic morphine. Consistent with its analgesic and respiratory depressant properties, M6G binds to the p-opioid receptor in a naloxone-reversible manner. Although the affinity of M6G for the mu-opioid receptor is similar to or slightly less than that of morphine, preclinical studies in rodents show that M6G is one to two orders of magnitude more potent than morphine when administered by central routes. This major discrepancy between the markedly higher intrinsic antinociceptive potency of M6G relative to morphine, despite their similar p-opioid receptor binding affinities, is difficult to reconcile. It has been proposed that M6G mediates its pain-relieving effects through a novel 'M6G opioid receptor', while others have argued that M6G may have higher efficacy than morphine for transduction of intracellular events. When administered by parenteral routes to rodents, M6G's antinociceptive potency is no more than twofold higher than morphine. In humans, the analgesic efficacy and respiratory depressant potency of M6G relative to morphine have been assessed in a number of short-term studies involving the intrathecal or intravenous routes of administration. For example, in hip replacement patients, intrathecal M6G provided excellent postoperative analgesia but the occurrence of late respiratory depression in 10% of these patients raised serious concern about safety. In postoperative patients, intravenous M6G administered by means of patient-controlled analgesia (PCA), or bolus plus PCA, produced no analgesia in one study and limited analgesia in another. Similarly, there was a lack of significant analgesia in healthy volunteers who received intravenous M6G for the alleviation of experimental pain (carbon dioxide applied to the nasal mucosa). In contrast, satisfactory analgesia was produced by bolus doses of intravenous M6G administered to patients with cancer pain, and to healthy volunteers with experimentally-induced ischaemic, electrical or thermal (ice water) pain. Studies to date in healthy volunteers suggest that intravenous M6G may be a less potent respiratory depressant and have a lower propensity for producing nausea and vomiting than morphine. However, it is unclear whether equi-analgesic doses of M6G and morphine were compared. Clearly, more extensive short-term trials, together with studies involving chronic M6G administration, are necessary before the potential clinical utility of M6G as an analgesic drug in its own right can be determined.

CemaT1 is an active transposon within the Caenorhabditis elegans genome

The maT clade of transposons is a group of transposable elements intermediate in sequence and predicted protein structure to mariner and T-C transposons, with a distribution thus far limited to a few invertebrate species. In the nematode Caenorhabditis elegans, there are eight copies of CemaT1 that are predicted to encode a functional transposase, with five copies being >99% identical. We present evidence, based on searches of publicly available databases and on PCR-based mobility assays, that the CemaT1 transposase is expressed in C. elegans and that the CemaT transposons are capable of excising in both somatic and germline tissues. We also show that the frequency of CemaT1 excisions within the genome of the N2 strain of C. elegans is comparable to that of the Tc1 transposon. However, unlike T-C transposons in mutator strains of C elegans, maT transposons do not exhibit increased frequencies of mobility, suggesting that maT is not regulated by the same factors that control T-C activity in these strains. Finally, we show that CemaT1 transposons are capable of precise transpositions as well as orientation inversions at some loci, and thereby become members of an increasing number of identified active transposons within the C. elegans genome. (C) 2004 Elsevier B.V. All rights reserved.

Modal characteristics of a flexible beam with multiple distributed actuators

A flexible structure with surface-bonded piezoceramic patches is modelled using Timoshenko beam theory. Exact mode shapes and natural frequencies associated with the flexural motion are computed for various piezoceramic distributed actuator arrangements. The effects of patch placement and of shear on the modal characteristics are demonstrated using a cantilevered beam as an example. Perfect bonding of the piezoceramic to the beam substructure is assumed, and for the purposes of this paper only passive piezoceramic properties are considered. The modelling technique and results obtained in a closed form are intended to assist investigations into the modelling and control of active structures with surface-bonded piezoceramic actuators. (C) 2003 Elsevier Science Ltd. All rights reserved.

The effect of weightbearing exercise with low frequency, whole body vibration on lumbosacral proprioception: A pilot study on normal subjects

Patients with low back pain (LBP) often present with impaired proprioception of the lumbopelvic region. For this reason, proprioception training usually forms part of the rehabilitation protocols. New exercise equipment that produces whole body, low frequency vibration (WBV) has been developed to improve muscle function, and reportedly improves proprioception. The aim of this pilot study was to investigate whether weightbearing exercise given in conjunction with WBV would affect lumbosacral position sense in healthy individuals. For this purpose, twenty-five young individuals with no LBP were assigned randomly to an experimental or control group. The experimental group received WBV for five minutes while holding a static, semi-squat position. The control group adopted the same weightbearing position for equal time but received no vibration. A two-dimensional motion analysis system measured the repositioning accuracy of pelvic tilting in standing. The experimental (WBV) group demonstrated a significant improvement in repositioning accuracy over time (mean 0.78 degrees) representing 39% improvement. It was concluded that WBV may induce improvements in lumbosacral repositioning accuracy when combined with a weightbearing exercise. Future studies with WBV should focus on evaluating its effects with different types of exercise, the exercise time needed for optimal outcomes, and the effects on proprioception deficits in LBP patients.

The effect of active immunization against adrenocorticotropic hormone on cortisol, beta-endorphin, vocalization, and growth in pigs

Because the poor growth performance of intensively housed pigs is associated with increased circulating glucocorticoid concentrations, we investigated the effects of glucocorticoid suppression by inducing a humoral immune response to ACTH on physiological and production variables in growing pigs. Grower pigs (28.6 0.9 kg) were immunized with amino acids 1 through 24 of ACTH conjugated to ovalbumin and suspended in diethylaminoethyl (DEAE) dextran-adjuvant or adjuvant alone (control) on d 1, 28, and 56. The ACTH-specific antibody titers generated suppressed increases in cortisol concentrations on d 63 in response to an acute stressor (P = 0.002; control = 71 +/- 8.2 ng/ mL; ACTH-immune = 43 +/- 4.9 ng/mL) without altering basal concentrations. Plasma beta-endorphin concentrations were also increased (P < 0.001) on d 63 (control = 18 +/- 2.1 ng/mL; ACTH-immune = 63 +/- 7.3 ng/mL), presumably because of a release from negative feedback on the expression of proopiomelanocortin in pituitary corticotropes. Immunization against ACTH did not alter ADG (P = 0.120; control = 1,077 25; ACTH-immune = 1,143 25 g) or ADFI (P = 0.64; control = 2,719 42; ACTH-immune = 2,749 42 g) and did not modify behavior (P = 0.681) assessed by measuring vocalization in response to acute restraint. In summary, suppression of stress-induced cortisol responses through ACTH immunization increased beta-endorphin concentrations, but it did not modify ADG, ADFI, or restraint vocalization score in growing pigs.

Changes in joint stability with muscle contraction measured from transmission of mechanical vibration

A non-invasive in vivo technique was developed to evaluate changes in wrist joint stability properties induced by increased co-activation of the forearm muscles in a gripping task. Mechanical vibration at 45, 50 and 55 Hz was applied to the radial head in ten healthy volunteers. Vibrations of the styloid process of the radius and the distal end of the metacarpal bone of the index finger were measured with triaxial accelerometers. Joint stability properties were quantified by the transfer function gain between accelerations on either side of the wrist-joint. Gain was calculated with the muscles at rest and at five force levels ranging from 5% to 25% of maximum grip force (%MF). During contraction the gain was significantly greater than in control trial (0%MF) for all contractions levels at 45 and 50 Hz and a trend for 15%MF and higher at 55 Hz. Group means of contraction force and gain were significantly correlated at 45 (R-2 = 0.98) and 50 Hz (R-2 = 0.72), but not at 55 Hz (R-2 = 0.10). In conclusion, vibration transmission gain may provide a method to evaluate changes in joint stability properties. (c) 2005 Published by Elsevier Ltd.

Highly demanding resistive vibration exercise program is tolerated during 56 days of strict bed-rest

Several studies have tried to find countermeasures against musculoskeletal de-conditioning during bed-rest, but none of them yielded decisive results. We hypothesised that resistive vibration exercise (RVE) might be a suitable training modality. We have therefore carried out a bed-rest study to evaluate its feasibility and efficacy during 56 days of bed-rest. Twenty healthy male volunteers aged 24 to 43 years were recruited and, after medical check-ups, randomised to a non-exercising control (Ctrl) group or a group that performed RVE 11 times per week. Strict bed-rest was controlled by video surveillance. The diet was controlled. RVE was performed in supine position, with a static force component of about twice the body weight and a smaller dynamic force component. RVE comprised four different units (squats, heel raises, toe raises, kicks), each of which lasted 60 - 100 seconds. Pre and post exercise levels of lactate were measured once weekly. Body weight was measured daily on a bed scale. Pain questionnaires were obtained in regular intervals during and after the bed-rest. Vibration frequency was set to 19 Hz at the beginning and progressed to 25.9 Hz (SD 1.9) at the end of the study, suggesting that the dynamic force component increased by 90%. The maximum sustainable exercise time for squat exercise increased from 86 s (SD 21) on day 11 of the BR to 176 s (SD 73) on day 53 (p = 0.006). On the same days, post-exercise lactate levels increased from 6.9 mmol/l (SD2.3) to 9.2 mmol/l (SD 3.5, p = 0.01). On average, body weight was unchanged in both groups during bed-rest, but single individuals in both groups depicted significant weight changes ranging from -10% to + d10% (p < 0.001). Lower limb pain was more frequent during bed-rest in the RVE subjects than in Ctrl (p = 0.035). During early recovery, subjects of both groups suffered from muscle pain to a comparable extent, but foot pain was more common in Ctrl than in RVE (p = 0.013 for plantar pain, p = 0.074 for dorsal foot pain). Our results indicate that RVE is feasible twice daily during bed-rest in young healthy males, provided that one afternoon and one entire day per week are free. Exercise progression, mainly by progression of vibration frequency, yielded increases in maximum sustainable exercise time and blood lactate. In conclusion, RVE as performed in this study, appears to be safe.

Biodegradation of the cyanobacterial toxin microcystin LR in natural water and biologically active slow sand filters

A bacterium (MJ-PV) previously demonstrated to degrade the cyanobacterial toxin microcystin LR, was investigated for bioremediation applications in natural water microcosms and biologically active slow sand filters. Enhanced degradation of microcystin LR was observed with inoculated (1 x 10(6) cell/mL) treatments of river water dosed with microcystin LR (> 80% degradation within 2 days) compared to uninoculated controls. Inoculation of MJ-PV at lower concentrations (1 x 10(2)-1 x 10(5)cells/mL) also demonstrated enhanced microcystin LR degradation over control treatments. Polymerase chain reactions (PCR) specifically targeting amplification of 16S rDNA of MJ-PV and the gene responsible for initial degradation of microcystin LR (mlrA) were successfully applied to monitor the presence of the bacterium in experimental trials. No amplified products indicative of an endemic MJ-PV population were observed in uninoculated treatments indicating other bacterial strains were active in degradation of microcystin LR, Pilot scale biologically active slow sand filters demonstrated degradation of microcystin LR irrespective of MJ-PV bacterial inoculation. PCR analysis detected the MJ-PV population at all locations within the sand filters where microcystin degradation was measured. Despite not observing enhanced degradation of microcystin LR in inoculated columns compared to uninoculated column, these studies demonstrate the effectiveness of a low-technology water treatment system like biologically active slow sand filters for removal of microcystins from reticulated water supplies. Crown Copyright (c) 2006 Published by Elsevier Ltd. All rights reserved.

Disrupted cortical proprioceptive representation evokes symptoms of peculiarity, foreignness and swelling, but not pain

Objectives. It has been proposed that disruption of the internal proprioceptive representation, via incongruent sensory input, may underpin pathological pain states, but experimental evidence relies on conflicting visual input, which is not clinically relevant. We aimed to determine the symptomatic effect of incongruent proprioceptive input, imparted by vibration of the wrist tendons, which evokes the illusion of perpetual wrist flexion and disrupts cortical proprioceptive representation. Methods. Twenty-nine healthy and naive volunteers reported symptoms during five conditions: control, active and passive wrist flexion, extensor carpi radialis tendon vibration to evoke illusion of perpetual wrist flexion, and ulnar styloid (sham) vibration. No advice was given about possible illusions. Results. Twenty-one subjects reported the illusion of perpetual wrist flexion during tendon vibration. There was no effect of condition or of whether or not subjects reported an illusion on discomfort/pain (P > 0.28). Peculiarity, swelling and foreignness were greater during tendon vibration than during the other conditions, and greater during tendon vibration in those who reported an illusion of wrist flexion than in those who did not (P < 0.05 for all). Symptoms were reported by at least two subjects in each condition and four subjects reported systemic symptoms (e.g. nausea). Conclusions. In healthy volunteers, incongruent proprioceptive input does not cause discomfort or pain but does evoke feelings of peculiarity, swelling and foreignness in the limb.

Reversible active switching of the mechanical properties of a peptide film at a fluid-fluid interface

Designer peptides have recently been developed as building blocks for novel self-assembled materials with stimuli-responsive properties. To date, such materials have been based on self-assembly in bulk aqueous solution or at solid-fluid interfaces. We have designed a 21-residue peptide, AM1, as a stimuli-responsive surfactant that switches molecular architectures at a fluid-fluid interface in response to changes in bulk aqueous solution composition. In the presence of divalent zinc at neutral pH, the peptide forms a mechanically strong 'film state'. In the absence of metal ions or at acid pH, the peptide adsorbs to form a mobile 'detergent state'. The two interfacial states can be actively and reversibly switched. Switching between the two states by a change in pH or the addition of a chelating agent leads to rapid emulsion coalescence or foam collapse. This work introduces a new class of surfactants that offer an environmentally friendly approach to control the stability of interfaces in foams, emulsions and fluid-fluid interfaces more generally.

Illusory changes in head position induced by neck muscle vibration can alter the perception of elbow position

Acuity for elbow joint position sense (JPS) is reduced when head position is modified. Movement of the head is associated with biomechanical changes in the neck and shoulder musculoskeletal system, which may explain changes in elbow JPS. The present study aimed to determine whether elbow JPS is also influenced by illusory changes in head position. Simultaneous vibration of sternocleidomastoid (SCM) and the contralateral splenius was applied to 14 healthy adult human subjects. Muscle vibration or passive head rotation was introduced between presentation and reproduction of a target elbow position. Ten out of 14 subjects reported illusions consistent with lengthening of the vibrated muscles. In these 10 subjects, absolute error for elbow JPS increased with left SCM/right splenius vibration but not with right SCM/left splenius vibration. Absolute error also increased with right rotation, with a trend for increased error with left rotation. These results demonstrated that both actual and illusory changes in head position are associated with diminished acuity for elbow JPS, suggesting that the influence of head position on upper limb JPS depends, at least partially, on perceived head position.