A century of exercise physiology: key concepts in muscle energetics.

In the mid-nineteenth century, the concept of muscle behaving like a stretched spring was developed. This elastic model of contraction predicted that the energy available to perform work was established at the start of a contraction. Despite several studies showing evidence inconsistent with the elastic model, it persisted into the twentieth century. In 1923, W. O. Fenn published a paper in which he presented evidence that appeared to clearly refute the elastic model. Fenn showed that when a muscle performs work it produces more heat than when contracting isometrically. He proposed that energy for performing work was only made available in a muscle as and when that work was performed. However, his ideas were not adopted and it was only after 15 years of technical developments that in 1938 A. V. Hill performed experiments that conclusively disproved the elastic model and supported Fenn's conclusions. Hill showed that the rate of heat production increased as a muscle made the transition from isometric to working contraction. Understanding the basis of the phenomenon observed by Fenn and Hill required another 40 years in which the processes that generate force and work in muscle and the associated scheme of biochemical reactions were established. Demonstration of the biochemical equivalent of Hill's observations-changes in rate of ATP splitting when performing work-in 1999 was possible through further technical advances. The concept that the energy, from ATP splitting, required to perform work is dynamically modulated in accord with the loads a muscle encounters when contracting is key to understanding muscle energetics.

Components of activation heat in skeletal muscle.

Activation heat (qA) production by muscle is the thermal accompaniment of the release of Ca2+ from the sarcoplasmic reticulum (SR) into the cytoplasm, its interactions with regulatory proteins and other cytoplasmic Ca2+ buffers and its return to the SR. The contribution of different Ca2+-related reactions to qA is difficult to determine empirically and therefore, for this study, a mathematical model was developed to describe Ca2+ movements and accompanying thermal changes in muscle fibres in response to stimulation. The major sources of heat within a few milliseconds of the initiation of Ca2+ release are Ca2+ binding to Tn and Pv. Ca2+ binding to ATP produces a relatively small amount of heat. Ca2+ dissociation from ATP and Tn, with heat absorption, are of similar time course to the decline of force. In muscle lacking Pv (e.g. mouse soleus), Ca2+ is then rapidly pumped into the SR. In muscles with Pv, Ca2+ that dissociates from Tn and ATP binds to Pv and then dissociates slowly (over 10 s of seconds) and is then pumped into the SR; the net effect of these two processes is heat absorption. It is proposed that this underlies Hill's "negative delayed heat". After all the Ca2+ is returned to the SR, qA is proportional to the amount of Ca2+ released into the cytoplasm. In muscles with Pv this is 20-60 s after Ca2+ release; in muscles without Pv, all Ca2+ is returned to the SR soon after the end of force relaxation.

Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease.

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean difference: -4.9%, 95% CI: -16.9, 7.1, P = 0.41). Secondary endpoints did not show significant differences between the groups either. A post hoc analysis found nine (43%) patients in the active group but no placebo patients with a large clinically important motor improvement (≥10 points) in the OFF state (P = 0.0008). 18F-DOPA PET imaging demonstrated a significantly increased uptake throughout the putamen only in the active group, ranging from 25% (left anterior putamen; P = 0.0009) to 100% (both posterior putamina; P < 0.0001). GDNF appeared to be well tolerated and safe, and no drug-related serious adverse events were reported. The study did not meet its primary endpoint. 18F-DOPA imaging, however, suggested that intermittent convection-enhanced delivery of GDNF produced a putamen-wide tissue engagement effect, overcoming prior delivery limitations. Potential reasons for not proving clinical benefit at 40 weeks are discussed.

Mini Dental Implants in the Management of The Atrophic Maxilla and Mandible: A New Implant Design and Preliminary Results.

Although the edentulous population in the UK is falling, those that are rendered edentulous are becoming edentate later in life and with significantly resorbed ridges. This creates a challenge because the management of such patients and their ability to adapt to new dentures is impaired later in life. Despite widespread endorsement of two implants to retain lower complete dentures, the inability to comply has resulted in elderly patients with compromised ability to function and unable to eat a healthy diet. Mini dental implants may offer an ideal solution for the elderly edentulous population who may not be keen on invasive surgery for the placement of conventional dental implants. Further work is required to show the longevity of these restorations, however, existing research and clinical experience show that they potentially offer a simple solution to this group of patients. This paper presents the development of a new design of mini implant, based on clinical problems encountered during a pilot randomised controlled trial. The design of the new implant specifically aims to overcome problems in managing severely atrophic ridges. A preliminary survival study shows survival rates to be equivalent to other mini dental implants and highly satisfactory in the short to medium term.

Energy demand and supply in human skeletal muscle.

The energy required for muscle contraction is provided by the breakdown of ATP but the amount of ATP in muscles cells is sufficient to power only a short duration of contraction. Buffering of ATP by phosphocreatine, a reaction catalysed by creatine kinase, extends the duration of activity possible but sustained activity depends on continual regeneration of PCr. This is achieved using ATP generated by oxidative processes and, during intense activity, by anaerobic glycolysis. The rate of ATP breakdown ranges from 70 to 140 mM min-1 during isometric contractions of various intensity to as much as 400 mM min-1 during intense, dynamic activity. The maximum rate of oxidative energy supply in untrained people is ~50 mM min-1 which, if the contraction duty cycle is 0.5 as is often the case in cyclic activity, is sufficient to match an ATP breakdown rate during contraction of 100 mM min-1. During brief, intense activity the rate of ATP turnover can exceed the rates of PCr regeneration by combined oxidative and glycolytic energy supply, resulting in a net decrease in PCr concentration. Glycolysis has the capacity to produce between 30 and 50 mM of ATP so that, for example, anaerobic glycolysis could provide ATP at an average of 100 mM min-1 over 30 s of exhausting activity. The creatine kinase reaction plays an important role not only in buffering ATP but also in communicating energy demand from sites of ATP breakdown to the mitochondria. In that role, creatine kinases acts to slow and attenuate the response of mitochondria to changes in energy demand.

Efficiency and cross-bridge work output of skeletal muscle is decreased at low levels of activation.

The purpose of this study was to determine how the mechanical efficiency of skeletal muscle is affected by level of activation. Experiments were performed in vitro (35 °C) using bundles of fibres from fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles of mice. Measurements were made of the total work and heat produced in response to 10 brief contractions. Mechanical efficiency was the ratio of total work performed to (total heat produced + work performed). Level of activation was varied by altering stimulation frequency between 40 and 160 Hz. Efficiency did not differ significantly between the two muscle types but was significantly lower using 40 Hz stimulation (mean efficiency ± SEM, 0.092 ± 0.012, n = 12, averaged across EDL and soleus) than at any of the other frequencies (160 Hz: 0.147 ± 0.007, n = 12). Measurements of the partitioning of energy output between force-dependent and force-independent components enabled calculation of the amount of Ca(2+) released and number of cross-bridge cycles performed during the contractions. At 40 Hz stimulation frequency, less Ca(2+) was released than at higher frequencies and fewer cross-bridge cycles were performed. Furthermore, less work was performed in each cross-bridge cycle. It is concluded that skeletal muscles are less efficient at low levels of activation than when fully activated and this indicates that level of activation affects not only the number of cycling cross-bridges but also the ability of individual cross-bridges to perform work.

The energetics of muscle contractions resembling in vivo performance.

Muscle energetics has expanded into the study of contractions that resemble in vivo muscle activity. A summary is provided of experiments of this type and what they have added to our understanding of muscle function and effects of compliant tendons, as well as the new questions raised about the efficiency of energy transduction in muscle.

Advances in understanding the energetics of muscle contraction.

Muscle energetics encompasses the relationships between mechanical performance and the biochemical and thermal changes that occur during muscular activity. The biochemical reactions that underpin contraction are described and the way in which these are manifest in experimental recordings, as initial and recovery heat, is illustrated. Energy use during contraction can be partitioned into that related to cross-bridge force generation and that associated with activation by Ca2+. Activation processes account for 25-45% of ATP turnover in an isometric contraction, varying amongst muscles. Muscle energy use during contraction depends on the nature of the contraction. When shortening muscles produce less force than when contracting isometrically but use energy at a greater rate. These characteristics reflect more rapid cross-bridge cycling when shortening. When lengthening, muscles produce more force than in an isometric contraction but use energy at a lower rate. In that case, cross-bridges cycle but via a pathway in which ATP splitting is not completed. Shortening muscles convert part of the free energy available from ATP hydrolysis into work with the remainder appearing as heat. In the most efficient muscle studied, that of a tortoise, cross-bridges convert a maximum of 47% of the available energy into work. In most other muscles, only 20-30% of the free energy from ATP hydrolysis is converted into work.

Quantifying Ca2+ release and inactivation of Ca2+ release in fast- and slow-twitch muscles.

The aims of this study were to quantify the Ca(2+) release underlying twitch contractions of mammalian fast- and slow-twitch muscle and to comprehensively describe the transient inactivation of Ca(2+) release following a stimulus. Experiments were performed using bundles of fibres from mouse extensor digitorum longus (EDL) and soleus muscles. Ca(2+) release was quantified from the amount of ATP used to remove Ca(2+) from the myoplasm following stimulation. ATP turnover by crossbridges was blocked pharmacologically (N-benzyl-p-toluenesulphonamide for EDL, blebbistatin for soleus) and muscle heat production was used as an index of Ca(2+) pump ATP turnover. At 20°C, Ca(2+) release in response to a single stimulus was 34 and 84 µmol (kg muscle)(-1) for soleus and EDL, respectively, and increased with temperature (30°C: soleus, 61 µmol kg(-1); EDL, 168 µmol kg(-1)). Delivery of another stimulus within 100 ms of the first produced a smaller Ca(2+) release. The maximum magnitude of the decrease in Ca(2+) release was greater in EDL than soleus. Ca(2+) release recovered with an exponential time course which was faster in EDL (mean time constant at 20°C, 32.1 ms) than soleus (65.6 ms) and faster at 30°C than at 20°C. The amounts of Ca(2+) released and crossbridge cycles performed are consistent with a scheme in which Ca(2+) binding to troponin-C allowed an average of ∼1.7 crossbridge cycles in the two muscles.

First Report of Cylindrocladiella parva as a Grapevine Pathogen in New Zealand.

Isolates morphologically identified as Cylindrocladiella parva were isolated from characteristic black foot symptoms on a grapevine (Vitis vinifera) rooted on 101-14 rootstock from Central Otago in 2005 and 101-14 rootstocks from a nursery in the Auckland Region in 2007 and 2008. On potato dextrose agar, the isolates initially produced cottony, white mycelia that turned grayish cream or golden cream within 10 days, the initially tawny colony undersides becoming dark brown with age. Conidia (0 to 1 septate; 16.4 to 17.0 [16.7] × 2.3 to 2.6 [2.5] µm) and abundant chlamydospores were produced. To confirm identity of the isolates, genomic DNA was extracted and the ribosomal DNA (rDNA) and ß-tubulin gene were amplified and sequenced (3,4). Sequences of the PCR products were compared with sequences in GenBank. The rDNA (535 bp) and ß-tubulin (297 bp) sequences of the four isolates were 100 and 99% identical, respectively, to reported sequences of C. parva in GenBank (AY793454, grapevine isolate (4)/AY793455 for rDNA; AY793486/AY793488, grapevine isolate (4)/AY793489/HM034822 for ß-tubulin). Although C. parva was previously isolated from grapevines in New Zealand (2) and rootstocks of mature grapevines, cuttings, and graft unions of grafted young grapevines in South Africa (4), its role as a pathogen of Vitis spp. has not been confirmed (2,4). However, it has been reported as a pathogen of Eucalyptus spp. (1) and was also isolated from Telopea speciosissima and Macadamia integrifolia in New Zealand (2,4). The C. parva isolates were tested as a mixed inoculum (four isolates) for pathogenicity on roots of 10 grapevine rootstock plants each of cvs. 101-14 and Schwarzmann (Sch). The rootstocks were grown in potting mix for 4 months, after which the root systems of all vines were wounded with an asparagus knife with a sharp, square tip, driven vertically down into the soil at four equidistant locations approximately 8 cm from the trunk. Each plant was inoculated with 50 ml of the mixed-isolate conidial suspension (106/ml), or 50 ml water (controls), followed by 50 ml of water. After 7 months of growth, the plants were harvested. For C. parva-inoculated plants, internal blackening of the stem base tissue was observed. Isolations from surface-sterilized trunk bases recovered C. parva from four and nine plants of 101-14 and Sch, respectively, with C. parva infections in 25 and 48%, respectively, of the four wood pieces taken per plant. Plants inoculated with water had no blackening and no C. parva was isolated from their stem bases. Mean shoot dry weights of inoculated plants (17.9 and 15.0 g for 101-14 and Sch, respectively) were significantly lower (P = 0.035) than noninoculated controls (26.5 and 20.0 g for 101-14 and Sch, respectively). Mean root dry weights were reduced by C. parva inoculation, although not significantly (32.7 and 27.0 g for C. parva inoculated 101-14 and Sch, respectively, and 36.2 and 27.4 g for control 101-14 and Sch, respectively). To our knowledge, this is the first report of C. parva as a pathogen of grapevines (2,4) and suggests that along with Cylindrocarpon spp., C. parva is part of the pathogen complex responsible for black foot of grapevines. References: (1) P. W. Crous et al. Plant Pathol. 42:302, 1993. (2) P. D. Gadgil et al. Fungi on Trees and Shrubs in New Zealand. Fungal Diversity Press, Hong Kong, 2005. (3) N. L. Glass and G. C. Donaldson. Appl. Environ. Microbiol. 61:1323, 1995. (4) G. J. van Coller et al. Australas. Plant Pathol. 34:489, 2005.

Dental dilemmas: endodontics or dental implants?

This narrative review explores treatment planning options in restorative dentistry. The growth of dental implants, as an accessible and predictable treatment option, gives practitioners a useful tool for managing the missing tooth or teeth with a hopeless prognosis. Traditionally, endodontics and fixed prosthodontics have been used to restore teeth and spaces where the outlook for such treatment appears reasonable. Practitioners may, however, question the predictability and cost effectiveness of such an approach where, at times, it might appear that replacement of a compromised tooth with a dental implant could be a more predictable option. The evidence base for these treatment options is explored and discussed, and suggestions are made for future management strategies.

Historical Perspective: Heat production and chemical change in muscle. Roger C. Woledge.

The objective of this article is to provide an historical perspective on a review of "Heat production and chemical change in muscle" written by Roger C. Woledge and published in Progress in Biophysics and Molecular Biology 50 years ago. We first provide a brief but broad summary of the history of muscle chemistry prior to 1971 and then address the central theme of the 1971 review - that of energy balance. Energy balance is a method to establish whether all the energetically significant biochemical reactions accompanying muscle contraction have been identified. Woledge adopted the method to compare the measured enthalpy output (i.e., the sum of the heat output and work output) to that expected from the extent of known biochemical reactions. Prior work had suggested that the observed and expected enthalpy outputs were similar but Woledge proposed that the expected heat had been overestimated and that, hence, there must be an unidentified reaction that accounted for as much as half the heat produced by a contracting muscle. We describe investigations carried out after the review that vindicated that view, ultimately characterising the processes producing the unexplained enthalpy which, in turn, led to identification of the hitherto unknown reaction. Those experiments and a more recent resurrection of the approach using fluorescent probes to monitor ATP turnover have now accounted for the processes that underlie the complex time courses of muscle heat production and ATP turnover during contraction, at least in the classical frog sartorius muscle preparation. However, the few studies performed on mammalian muscles since then have produced results that are difficult to reconcile with the ideas derived from energy balance studies of amphibian and fish muscles, thereby suggesting a new objective for energy balance studies.

Is the efficiency of mammalian (mouse) skeletal muscle temperature dependent?

Myosin crossbridges in muscle convert chemical energy into mechanical energy. Reported values for crossbridge efficiency in human muscles are high compared to values measured in vitro using muscles of other mammalian species. Most in vitro muscle experiments have been performed at temperatures lower than mammalian physiological temperature, raising the possibility that human efficiency values are higher than those of isolated preparations because efficiency is temperature dependent. The aim of this study was to determine the effect of temperature on the efficiency of isolated mammalian (mouse) muscle. Measurements were made of the power output and heat production of bundles of muscle fibres from the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles during isovelocity shortening. Mechanical efficiency was defined as the ratio of power output to rate of enthalpy output, where rate of enthalpy output was the sum of the power output and rate of heat output. Experiments were performed at 20, 25 and 30◦C. Maximum efficiency of EDL muscles was independent of temperature; the highest value was 0.31}0.01 (n =5) at 30◦C. Maximum efficiency of soleus preparations was slightly but significantly higher at 25 and 30◦C than at 20◦C; the maximum mean value was 0.48±0.02 (n =7) at 25◦C. It was concluded that maximum mechanical efficiency of isolated mouse muscle was little affected by temperature between 20 and 30◦C and that it is unlikely that differences in temperature account for the relatively high efficiency of human muscle in vivo compared to isolated mammalian muscles.

Effect of phosphate and temperature on force exerted by white muscle fibres from dogfish.

Effects of Pi (inorganic phosphate) are relevant to the in vivo function of muscle because Pi is one of the products of ATP hydrolysis by actomyosin and by the sarcoplasmic reticulum Ca(2+) pump. We have measured the Pi sensitivity of force produced by permeabilized muscle fibres from dogfish (Scyliorhinus canicula) and rabbit. The activation conditions for dogfish fibres were crucial: fibres activated from the relaxed state at 5, 12, and 20 degrees C were sensitive to Pi, whereas fibres activated from rigor at 12 degrees C were insensitive to Pi in the range 5-25 mmol l(-1). Rabbit fibres activated from rigor were sensitive to Pi. Pi sensitivity of force produced by dogfish fibres activated from the relaxed state was greater below normal body temperature (12 degrees C for dogfish) in agreement with what is known for other species. The force-temperature relationship for dogfish fibres (intact and permeabilized fibres activated from relaxed) showed that at 12 degrees C, normal body temperature, the force was near to its maximum value.

The influence of tendon compliance on muscle power output and efficiency during cyclic contractions.

Muscle power output and efficiency during cyclical contractions are influenced by the timing and duration of stimulation of the muscle and the interaction of the muscle with its mechanical environment. It has been suggested that tendon compliance may reduce the energy required for power production from the muscle by reducing the required shortening of the muscle fibres. Theoretically this may allow the muscle to maintain both high power output and efficiency during cyclical contraction; however, this has yet to be demonstrated experimentally. To investigate how tendon compliance might act to increase muscle power output and/or efficiency, we attached artificial tendons of varying compliance to muscle fibre bundles in vitro and measured power output and mechanical efficiency during stretch-shorten cycles (2 Hz) with a range of stretch amplitudes and stimulation patterns. The results showed that peak power, average power output and efficiency (none of which can have direct contributions from the compliant tendon) all increased with increasing tendon compliance, presumably due to the tendon acting to minimise muscle energy use by allowing the muscle fibres to shorten at optimal speeds. Matching highly compliant tendons with a sufficiently large amplitude length change and appropriate stimulation pattern significantly increased the net muscle efficiency compared with stiff tendons acting at the same frequency. The maximum efficiency for compliant tendons was also similar to the highest value measured under constant velocity and force conditions, which suggests that tendon compliance can maximise muscle efficiency in the conditions tested here. These results provide experimental evidence that during constrained cyclical contractions, muscle power and efficiency can be enhanced with compliant tendons.

Efficiency of cross-bridges and mitochondria in mouse cardiac muscle.

The aim of this study was to make cellular-level measurements of the mechanical efficiency of mouse cardiac muscle and to use these measurements to determine (1) the work performed by a cross-bridge in one ATP-splitting cycle and (2) the fraction of the free energy available in metabolic substrates that is transferred by oxidative phosphorylation to free energy in ATP (i.e. mitochondrial thermodynamic efficiency). Experiments were performed using isolated left ventricular mouse papillary muscles (n = 9; studied at 27°C) and the myothermic technique. The production of work and heat was measured during and after 40 contractions at a contraction frequency of 2 Hz. Each contraction consisted of a brief isometric period followed by isovelocity shortening. Work output, heat output and enthalpy output were all independent of shortening velocity. Maximum initial mechanical efficiency (mean ± SEM) was 31.1 ± 1.3% and maximum net mechanical efficiency 16.9 ± 1.5%. It was calculated that the maximum work per cross-bridge cycle was 20 zJ, comparable to values for mouse skeletal muscle, and that mitochondrial thermodynamic efficiency was 72%. Analysis of data in the literature suggests that mitochondrial efficiency of cardiac muscle from other species is also likely to be between 70 and 80%.

Energetic consequences of mechanical loads.

In this brief review, we have focussed largely on the well-established, but essentially phenomenological, linear relationship between the energy expenditure of the heart (commonly assessed as the oxygen consumed per beat, oxygen consumption (VO2)) and the pressure-volume-area (PVA, the sum of pressure-volume work and a specified 'potential energy' term). We raise concerns regarding the propriety of ignoring work done during 'passive' ventricular enlargement during diastole as well as the work done against series elasticity during systole. We question the common assumption that the rate of basal metabolism is independent of ventricular volume, given the equally well-established Feng- or stretch-effect. Admittedly, each of these issues is more of conceptual than of quantitative import. We point out that the linearity of the enthalpy-PVA relation is now so well established that observed deviations from linearity are often ignored. Given that a one-dimensional equivalent of the linear VO2-PVA relation exists in papillary muscles, it seems clear that the phenomenon arises at the cellular level, rather than being a property of the intact heart. This leads us to discussion of the classes of crossbridge models that can be applied to the study of cardiac energetics. An admittedly superficial examination of the historical role played by Hooke's Law in theories of muscle contraction foreshadows deeper consideration of the thermodynamic constraints that must, in our opinion, guide the development of any mathematical model. We conclude that a satisfying understanding of the origin of the enthalpy-PVA relation awaits the development of such a model.

Temperature change as a probe of muscle crossbridge kinetics: a review and discussion.

Following the ideas introduced by Huxley (Huxley 1957, Prog. Biophys. Biophys. Chem. 7, 255-318), it is generally supposed that muscle contraction is produced by temporary links, called crossbridges, between myosin and actin filaments, which form and break in a cyclic process driven by ATP splitting. Here we consider the interaction of the energy in the crossbridge, in its various states, and the force exerted. We discuss experiments in which the mechanical state of the crossbridge is changed by imposed movement and the energetic consequence observed as heat output and the converse experiments in which the energy content is changed by altering temperature and the mechanical consequences are observed. The thermodynamic relationship between the experiments is explained and, at the first sight, the relationship between the results of these two types of experiment appears paradoxical. However, we describe here how both of them can be explained by a model in which mechanical and energetic changes in the crossbridges occur in separate steps in a branching cycle.

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease.

BACKGROUND: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen. OBJECTIVE: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. METHODS: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified. CONCLUSIONS: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Successful AV fistula creation does not lead to higher catheter use: the experience by the Northwest Renal Network 16 Vascular Access Quality Improvement Program. Four years follow-up.

BACKGROUND: In 2002, the Center for Medicare and Medicaid Services (CMS) required all 18 Renal Networks to participate in a Vascular Access Quality Improvement Program (QIP). The Northwest Renal Network (NWRN 16) chose to increase arteriovenous fistula (AVF) use. NWRN 16 hypothesized that strategies which targeted the improvement of AVF rate and the reduction of catheter use were the same. In December 2001, 44.2% of hemodialysis (HD) patients in the NWRN 16 received HD using an AVF which met the Dialysis Outcome Quality Initiative (K/DOQI) 40% AVF guideline for prevalent patients. However, 43% of HD facilities (2869 patients) had less than 40% of AVF and higher HD catheter rates than the average Network catheter rates (25.0 vs. 20.3%). To address the needs of underperforming facilities, NWRN 16 provided education and tools for their vascular access decision makers to promote AVF creation and catheter reduction. METHODS: In 2002, NWRN 16 sponsored four regional workshops targeted at nephrologists, vascular surgeons, HD nurses, and interventional radiologists. RESULTS: Percentage of AVFs in use in invited facilities increased from 31.3% pre-intervention to 56.2% at 4 yrs: 78% increase (99% confidence interval: 77.8% to 81.5%). Percentage of catheters increased from 25% to 25.8%: 3.2% change over 4 yrs (99% confidence interval: 2.5% to 4%). CONCLUSION: The success of Network 16's AVF interventions demonstrates the effectiveness of Network education promoting multidisciplinary teamwork, and innovative strategies to increase dramatically AVF use without substantial increase in catheter use.