Does creatine supplementation affect recovery speed of impulse above critical torque?

We previously reported that creatine supplementation improved intermittent isometric exercise performance by augmenting the total impulse performed above end-test torque (total IET'). However, our previous analyses did not enable mechanistic assessments. The objective of this study was to determine if creatine supplementation affected the IET' speed of recovery. To achieve this objective, we retrospectively analyzed our data using the IET' balance model to determine the time constant for the recovery of IET' (τIET'). Sixteen men were randomly allocated into creatine (N = 8) or placebo (N = 8) groups. Prior to supplementation, participants performed quadriceps all-out exercise to determine end-test torque (ET) and IET'. Participants then performed quadriceps exercise at ET + 10% until task-failure before supplementation (Baseline), until task-failure after supplementation (Creatine or Placebo), and until the Baseline time after supplementation (Creatine- or Placebo-Isotime). τIET' was faster than Baseline for Creatine (669 ± 98 vs 470 ± 66 s), but not Placebo (792 ± 166 vs 786 ± 161 s). The creatine-induced change in τIET' was inversely correlated with the creatine-induced changes in both the rate of peripheral fatigue development and time to task-failure. τIET' was inversely correlated with total IET' and ET in all conditions, but creatine supplementation shifted this relationship such that τIET' was faster for a given ET. Creatine supplementation, therefore, sped the recovery of IET' during intermittent isometric exercise, which was inversely related to the improvement in exercise performance. These findings support that the improvement in exercise performance after creatine supplementation was, at least in part, specific to effects on the physiological mechanisms that determine the IET' speed of recovery.HIGHLIGHTSSixteen healthy participants were randomly allocated to creatine supplementation or placebo groups.Creatine supplementation accelerated the time constant for the recovery of IET' (τIET').The time constant for the recovery of IET' (τIET') was inversely related to both the rate of peripheral fatigue development and the time to task failure.

Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular adenosine triphosphate (ATP) derived from respiration, and that ATP levels could be restored with coenzyme Q10 (CoQ10 ) supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10 . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants.

Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells.

With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.

Creatine supplementation attenuates the rate of fatigue development during intermittent isometric exercise performed above end-test torque.

NEW FINDINGS: What is the central question of this study? Does creatine supplementation augment the total torque impulse accumulated above end-test torque (IET) during severe-intensity knee-extensor exercise by attenuating the rate of decrease in peak potentiated twitch torque (PT)? What is the main finding and its importance? Creatine augmented the IET and attenuated the rate of decrease in both voluntary activation and PT during severe-intensity exercise. The IET was related to the rate of decrease in PT. These findings reveal an important role for the rates of neuromuscular fatigue development as key determinants of exercise tolerance within the severe domain. ABSTRACT: This study investigated the effect of creatine supplementation on exercise tolerance, total torque impulse accumulated above end-test torque (total IET) and neuromuscular fatigue development of the knee extensors during severe-intensity intermittent isometric exercise. Sixteen men were randomly allocated into Creatine (n = 8, 20 g day-1 for 5 days) or Placebo (n = 8) groups and performed knee-extensor maximal voluntary contraction (MVC) testing, all-out testing to determine end-test torque (ET) and the finite torque impulse accumulated above end-test torque (IET'), and three submaximal tests at ET + 10%: (i) time to task failure without supplementation (Baseline); (ii) time to task failure after creatine or placebo supplementation; and (iii) time matched to Baseline after creatine (Creatine-Isotime) or placebo (Placebo-Isotime) supplementation. Creatine supplementation significantly increased the time to task failure (Baseline = 572 ± 144 s versus Creatine = 833 ± 221 s) and total IET (Baseline = 5761 ± 1710  N m s versus Creatine = 7878 ± 1903 N m s), but there were no significant differences within the Placebo group. The percentage change pre- to postexercise in MVC, voluntary activation, peak potentiated twitch torque and integrated EMG during MVC were not significantly different between Baseline and Creatine but were all significantly attenuated in Creatine-Isotime compared with Baseline. There were no significant differences in these variables within the placebo group. The total IET was significantly correlated with the rates of change in potentiated twitch torque peak (r = 0.83-0.87) and rate of torque development (r = -0.83 to -0.87) for the submaximal tests to task failure. These findings reveal an important role for the rates of neuromuscular fatigue development as key determinants of exercise tolerance during severe-intensity intermittent isometric exercise.

Curcumin attenuates autoimmunity and renal injury in an experimental model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with prevalent hypertension and renal disease. To avoid side effects of immunosuppressive drugs, alternative therapies are needed. Curcumin has been used in Eastern medicine for its anti-inflammatory and antioxidant properties. This study tested whether oral curcumin administration attenuates autoimmunity and renal injury during SLE. Female NZBWF1 (model of SLE) and NZW/LacJ (control) mice were administered curcumin (500 mg kg-1  day-1 , oral gavage) for 14 days in two separate groups beginning at either 26 or 32 weeks of age. Body weight and composition were monitored throughout the study. Immune activity was assessed by spleen weight, circulating dsDNA autoantibodies, and B lymphocytes. Renal injury (albumin excretion, glomerulosclerosis, blood urea nitrogen (BUN)) was measured as a hemodynamic function (glomerular filtration rate (GFR), mean arterial pressure (MAP)) in conscious mice. Body weight and composition were maintained in curcumin-treated SLE mice, but decreased in vehicle-treated SLE mice. Curcumin-treated SLE mice had lower spleen weight and renal injury (glomerulosclerosis) compared to vehicle-treated SLE mice when treatment started at 26 weeks of age. When curcumin treatment started at 32 weeks of age, renal injury (glomerulosclerosis, BUN) was reduced in SLE mice compared to vehicle-treated SLE mice. GFR was reduced, and MAP was increased in vehicle-treated SLE mice compared to controls; however, these were not improved with curcumin. No significant changes were observed in curcumin-treated control mice. These data suggest that curcumin modulates autoimmune activity and may lessen renal injury in female mice with SLE.

Prolotherapy injections and physiotherapy used singly and in combination for lateral epicondylalgia: a single-blinded randomised clinical trial.

BACKGROUND: Lateral epicondylalgia (tennis elbow) is a common, debilitating and often treatment-resistant condition. Two treatments thought to address the pathology of lateral epicondylalgia are hypertonic glucose plus lignocaine injections (prolotherapy) and a physiotherapist guided manual therapy/exercise program (physiotherapy). This trial aimed to compare the short- and long-term clinical effectiveness, cost effectiveness, and safety of prolotherapy used singly and in combination with physiotherapy. METHODS: Using a single-blinded randomised clinical trial design, 120 participants with lateral epicondylalgia of at least 6 weeks' duration were randomly assigned to prolotherapy (4 sessions, monthly intervals), physiotherapy (weekly for 4 sessions) or combined (prolotherapy+physiotherapy). The Patient-Rated Tennis Elbow Evaluation (PRTEE) and participant global impression of change scores were assessed by blinded evaluators at baseline, 6, 12, 26 and 52 weeks. Success rate was defined as the percentage of participants indicating elbow condition was either 'much improved' or 'completely recovered.' Analysis was by intention-to-treat. RESULTS: Eighty-eight percent completed the 12-month assessment. At 52 weeks, there were substantial, significant improvements compared with baseline status for all outcomes and groups, but no significant differences between groups. The physiotherapy group exhibited greater reductions in PRTEE at 12 weeks than the prolotherapy group (p = 0.014). CONCLUSION: There were no significant differences amongst the Physiotherapy, Prolotherapy and Combined groups in PRTEE and global impression of change measures over the course of the 12-month trial. TRIAL REGISTRATION: ACTRN12612000993897 .

MicroRNA-21 ablation exacerbates aldosterone-mediated cardiac injury, remodeling, and dysfunction.

Primary aldosteronism is characterized by excess aldosterone secretion by the adrenal gland independent of the renin-angiotensin system and accounts for ~10% of hypertensive patients. Excess aldosterone causes cardiac hypertrophy, fibrosis, inflammation, and hypertension. The molecular mechanisms that trigger the onset and progression of aldosterone-mediated cardiac injury remain incompletely understood. MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that have been implicated in multiple cardiac pathologies; however, their regulation and role in aldosterone-mediated cardiac injury and dysfunction remains mostly unknown. We previously reported that microRNA-21 (miR-21) is the most upregulated miRNA by excess aldosterone in the left ventricle in a rat experimental model of primary aldosteronism. To elucidate the role of miR-21 in aldosterone-mediated cardiac injury and dysfunction, miR-21 knockout mice and their wild-type littermates were treated with aldosterone infusion and salt in the drinking water for 2 or 8 wk. miR-21 genetic ablation exacerbated aldosterone/salt-mediated cardiac hypertrophy and cardiomyocyte cross-sectional area. Furthermore, miR-21 genetic ablation increased the cardiac expression of fibrosis and inflammation markers and fetal gene program. miR-21 genetic ablation increased aldosterone/salt-mediated cardiac dysfunction but did not affect aldosterone/salt-mediated hypertension. miR-21 target gene Sprouty 2 may be implicated in the cardiac effects of miR-21 genetic ablation. Our study shows that miR-21 genetic ablation exacerbates aldosterone/salt-mediated cardiac hypertrophy, injury, and dysfunction blood pressure independently. These results suggest that miR-21 plays a protective role in the cardiac pathology triggered by excess aldosterone. Furthermore, miR-21 supplementation may be a novel therapeutic approach to abolish or mitigate excess aldosterone-mediated cardiovascular deleterious effects in primary aldosteronism.

Leadership Perspectives on Integrating Psychologists into Specialty Care Clinics: An Evolving Paradigm.

Integration of health psychologists into specialty care is a shift in the tertiary care construct that addresses all aspects of a patient's presentation, including psychiatric/social history, psychological well-being, and behavioral contributions to the disease process, assuring both optimal health outcomes and cost-effectiveness in a financially challenging healthcare environment. In this paper, we discuss leadership perspectives (physician and psychologists) on the factors involved in integrating a health psychologist into a busy tertiary care environment. Ultimately, we hope that this information provides a primer on how to frame a proposal for an integrated health psychologist emphasizing the elements important to senior medical leadership and administration. First, we briefly discuss the current payer framework, providing support for integration emphasizing costs and other metrics. Second, we introduce organizational structure models and strategies for integration. Lastly, we will discuss the unique skillset psychologists possess, and additional skills necessary, to be effective in the changing landscape of healthcare. We think this information is important both for leaders attempting to integrate a health psychologist into specialty care and for the early career health psychologist embarking on his/her first senior staff position.

Comorbidities, Concomitant Medications, and Diet as Factors Affecting Levothyroxine Therapy: Results of the CONTROL Surveillance Project.

BACKGROUND: The CONTROL Surveillance Project was a comprehensive patient-based survey conducted among hypothyroid patients undergoing treatment. The primary objective of the study was to specifically quantify the prevalence of factors adversely affecting levothyroxine therapy. METHODS: Participants were selected from a large proprietary database. Those eligible for the study completed a 21-question survey. RESULTS: Of the eligible hypothyroid patients, 925 (92.5%) were being treated with levothyroxine monotherapy. The mean age was 60.4 years; 755 (81.6%) were female and 168 (18.2%) were male. Almost half of those receiving levothyroxine (435, 47.0%) had at least one comorbid condition that could adversely affect its absorption: gastroesophageal reflux disease (33.8% of patients), irritable bowel syndrome (9.7%), lactose intolerance (7.8%), or a history of gastric bypass surgery or bowel resection (3.0%). Other factors reported by many patients that could adversely affect levothyroxine absorption included use of prescription medications (20.6%) and over-the-counter medications (34.3%) used to treat comorbid gastrointestinal (GI) conditions; use of dietary supplements (51.8%, primarily calcium and iron); and intake of foods/beverages high in fiber, iodine, or soy (68.0%). Of the 13.4% who reported difficulty controlling their hypothyroid symptoms, significantly more patients with comorbid GI conditions reported such difficulty (7.8 versus 5.6%, P < 0.01). Frequent changes in levothyroxine dosing (two or more dose changes in the past year) were reported by 8.0% of survey participants. Those with GI comorbidities were nearly twice as likely to have such changes (5.0 versus 3.0%, P < 0.01). CONCLUSION: Better initial workup of patients, including identification of relevant GI comorbidities and allergies, may help in the early detection of factors that may affect the performance of levothyroxine.

Toxicity and carcinogenicity studies of Ginkgo biloba extract in rat and mouse: liver, thyroid, and nose are targets.

Ginkgo biloba extract (GBE) is a popular herbal supplement that is used to improve circulation and brain function. In spite of widespread human exposure to relatively high doses over potentially long periods of time, there is a paucity of data from animal studies regarding the toxicity and carcinogenicity associated with GBE. In order to fill this knowledge gap, 3-month and 2-year toxicity and carcinogenicity studies with GBE administered by oral gavage to B6C3F1/N mice and F344/N rats were performed as part of the National Toxicology Program's Dietary Supplements and Herbal Medicines Initiative. The targets of GBE treatment were the liver, thyroid, and nose. These targets were consistent across exposure period, sex, and species, albeit with varying degrees of effect observed among studies. Key findings included a notably high incidence of hepatoblastomas in male and female mice and evidence of carcinogenic potential in the thyroid gland of both mice and rats. Various nonneoplastic lesions were observed beyond control levels in the liver, thyroid gland, and nose of rats and mice administered GBE. Although these results cannot be directly extrapolated to humans, the findings fill an important data gap in assessing risk associated with GBE use.

Resveratrol supplementation preserves long bone mass, microstructure, and strength in hindlimb-suspended old male rats.

Resveratrol has gained popularity as an "anti-aging" compound due to its antioxidant and anti-inflammatory properties. Few studies have investigated the role of resveratrol supplementation in the prevention of age-related bone loss and skeletal disuse despite increased inactivity and age-related bone loss in the elderly. The objective of the study was to investigate the effect of resveratrol supplementation on disuse and age-related bone loss. Old (age 33 months) Fischer 344 × Brown Norway male rats were provided either trans-resveratrol (12.5 mg/kg bw/day) or deionized distilled water by oral gavage for 21 days. Rats were hindlimb-suspended (HLS) or kept ambulatory (AMB) for 14 days. Both femora and tibiae were collected. Bone mass was measured by dual-energy X-ray absorptiometry and bone microstructure was determined by micro-computed tomography. HLS of old male rats accelerated loss of bone mineral content, decreased trabecular bone volume per unit of total volume, and increased trabecular separation. Resveratrol supplementation ameliorated bone demineralization and loss of bone microarchitecture in HLS old male rats. The peak force measured by the three-point bending test was reduced (P = 0.007) in HLS/control compared to AMB/control rats. Resveratrol supplementation ameliorated HLS-induced loss of femur strength. Plasma osteocalcin and alkaline phosphatase was higher (P < 0.04) and C-reactive protein was lower (P = 0.04) in old male rats given resveratrol. The bone protective effects of resveratrol appeared to be mediated through increased osteoblast bone formation, possibly due to reduced inflammation. Based on the results, resveratrol supplementation appeared to provide a feasible dietary therapy for preserving the skeletal system during disuse and age-related bone loss.

Complex histopathologic response in rat kidney to oral ß-myrcene: an unusual dose-related nephrosis and low-dose alpha2u-globulin nephropathy.

Oral gavage studies with ß-myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (α2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, α2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with α2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because ß-myrcene induced a complex spectrum of renal pathology, the α2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats.

Do frog-eating bats perceptually bind the complex components of frog calls?

The mating calls of male túngara frogs, Physalaemus pustulosus, attract intended (conspecific females) and unintended (eavesdropping predators and parasites) receivers. The calls are complex, having two components: a frequency-modulated "whine" followed by 0-7 harmonic bursts or "chucks". The whine is necessary and sufficient to elicit phonotaxis from females and the chuck enhances call attractiveness when it follows a whine. Although chucks are never made alone, females perceptually bind the whine and chuck when they are spatially separated. We tested whether an unintended receiver with independent evolution of phonotaxis, the frog-eating bat, Trachops cirrhosus, has converged with frogs in its auditory grouping of the call components. In contrast to frogs, bats approached chucks broadcast alone; when the chuck was spatially separated from the whine the bats preferentially approached the whine, and bats were sensitive to whine-chuck temporal sequence. This contrast suggests that although disparate taxa may be selected to respond to the same signals, different evolutionary histories, selective regimes, and neural and cognitive architectures may result in different weighting and grouping of signal components between generalist predators and conspecific mates.

Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial.

OBJECTIVE: Chronic lateral epicondylosis is common, debilitating, and often refractory. Prolotherapy (PrT) is an injection therapy for tendinopathy. The efficacy of two PrT solutions for chronic lateral epicondylosis was evaluated. DESIGN: This study is a three-arm randomized controlled trial. Twenty-six adults (32 elbows) with chronic lateral epicondylosis for 3 mos or longer were randomized to ultrasound-guided PrT with dextrose solution, ultrasound-guided PrT with dextrose-morrhuate sodium solution, or watchful waiting ("wait and see"). The primary outcome was the Patient-Rated Tennis Elbow Evaluation (100 points) at 4, 8, and 16 wks (all groups) and at 32 wks (PrT groups). The secondary outcomes included pain-free grip strength and magnetic resonance imaging severity score. RESULTS: The participants receiving PrT with dextrose and PrT with dextrose-morrhuate reported improved Patient-Rated Tennis Elbow Evaluation composite and subscale scores at 4, 8, and/or 16 wks compared with those in the wait-and-see group (P < 0.05). At 16 wks, compared with baseline, the PrT with dextrose and PrT with dextrose-morrhuate groups reported improved composite Patient-Rated Tennis Elbow Evaluation scores by a mean (SE) of 18.7 (9.6; 41.1%) and 17.5 (11.6; 53.5%) points, respectively. The grip strength of the participants receiving PrT with dextrose exceeded that of the PrT with dextrose-morrhuate and the wait and see at 8 and 16 wks (P < 0.05). There were no differences in magnetic resonance imaging scores. Satisfaction was high; there were no adverse events. CONCLUSIONS: PrT resulted in safe, significant improvement of elbow pain and function compared with baseline status and follow-up data and the wait-and-see control group. This pilot study suggests the need for a definitive trial.

Resveratrol supplementation influences bone properties in the tibia of hindlimb-suspended mature Fisher 344 × Brown Norway male rats.

The deleterious bone effects of mechanical unloading have been suggested to be due to oxidative stress and (or) inflammation. Resveratrol has both antioxidant and anti-inflammatory properties; therefore, the study's objective was to determine whether providing resveratrol in the low supplementation range for a short duration prevents bone loss during mechanical unloading. Mature (6 months old) Fischer 344 × Brown Norway male rats were hindlimb-suspended (HLS) or kept ambulatory for 14 days. Rats were provided either trans-resveratrol (RES; 12.5 mg/kg body mass per day) or deionized distilled water by oral gavage for 21 days (7 days prior to and during the 14 days of HLS). Bone mass was measured by dual energy X-ray absorptiometry. Bone microstructure was determined by microcomputed tomography. HLS of rats resulted in femur trabecular bone deterioration. Resveratrol supplementation did not attenuate trabecular bone deterioration in HLS rats. Unexpectedly, HLS-RES rats had the lowest tibial bone mineral content (P < 0.05), calcium content and lower cortical thickness (P < 0.05), and increased porosity compared with HLS/control rats. Plasma osteocalcin was also lower (P < 0.04) in HLS/resveratrol rats. There were no significant effects on plasma C-reactive protein, a marker of systemic inflammation, or total antioxidant capacity. However, HLS-RES rats showed a negative relationship (r(2) = 0.69, P = 0.02) between plasma osteocalcin and thiobarbituric acid reactive substances, a marker of lipid peroxidation. Based on the results, resveratrol supplementation of 6-month-old HLS male rats had no bone protective effects and possibly even detrimental bone effects.

An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents.

Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/day BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents.

Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up.

OBJECTIVE: The objective of this study was to determine whether prolotherapy, an injection-based complementary treatment for chronic musculoskeletal conditions, improves pain, stiffness, and function in adults with symptomatic knee osteoarthritis (KOA) compared to baseline status. DESIGN: This was a prospective, uncontrolled study with 1-year follow-up. SETTING: The study was conducted in an outpatient setting. PARTICIPANTS: Adults with at least 3 months of symptomatic KOA, recruited from clinical and community settings, participated in the study. INTERVENTIONS: Participants received extra-articular injections of 15% dextrose and intra-articular prolotherapy injections of 25% dextrose at 1, 5, and 9 weeks, with as-needed treatments at weeks 13 and 17. OUTCOME MEASURES: Primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC). Secondary outcome measure was the validated Knee Pain Scale (KPS). Tertiary outcome measure was procedure-related pain severity and participant satisfaction. RESULTS: Thirty-six (36) participants (60 ± 8.7 years old, 21 female) with moderate-to-severe KOA received an average of 4.3 ± 0.7 prolotherapy injection sessions over a 17-week treatment period and reported progressively improved scores during the 52-week study on WOMAC and KPS measures. Participants reported overall WOMAC score improvement 4 weeks after the first injection session (7.6 ± 2.4 points, 17.2%), and continued to improve through the 52-week follow-up (15.9 ± 2.5 points, p<0.001, 36.1%). KPS scores improved in both injected (p<0.001) and uninjected knees (p<0.05). Prescribed low-dose opioid analgesia effectively treated procedure-related pain. Satisfaction was high and there were no adverse events. Female gender, age 46-65 years old, and body-mass index of 25 kg/m(2) or less were associated with greater improvement on the WOMAC instrument. CONCLUSIONS: In adults with moderate to severe KOA, dextrose prolotherapy may result in safe, significant, sustained improvement of knee pain, function, and stiffness scores. Randomized multidisciplinary effectiveness trials including evaluation of potential disease modification are warranted to further assess the effects of prolotherapy for KOA.

Long-term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in aged mice.

This study analyzed the capacity of resveratrol, a naturally occurring polyphenol, to reduce aging-induced oxidative stress and protect against sarcopenia. Middle-aged (18 months) C57/BL6 mice were randomly assigned to receive either a control diet or a diet supplemented with 0.05% trans-resveratrol for 10 months. Young (6 months) and middle-aged (18 months) mice were used as controls. Resveratrol supplementation did not reduce the aging-associated loss of muscle mass or improve maximal isometric force production, but it appeared to preserve fast-twitch fiber contractile function. Resveratrol supplementation did not improve mitochondrial content, the subcellular localization of cytochrome c protein content, or PGC1 protein content. Resveratrol increased manganese superoxide dismutase (MnSOD), reduced hydrogen peroxide(,) and lipid peroxidation levels in muscle samples, but it was unable to significantly reduce protein carbonyl levels. The data suggest that resveratrol has a protective effect against aging-induced oxidative stress in skeletal muscle, likely through the upregulation of MnSOD activity, but sarcopenia was not attenuated by resveratrol.

A new generation of serotype chimeric infectivity-enhanced conditionally replicative adenovirals: the safety profile of ad5/3-Δ24 in advance of a phase I clinical trial in ovarian cancer patients.

Conditionally replicative adenoviral (CRAd) virotherapy represents a promising therapeutic approach for cancer. We have demonstrated that a serotype chimeric adenoviral 5/3 fiber-knob modification achieves enhanced ovarian cancer infectivity, conditional replication, and oncolytic activity. This study evaluated the safety of intraperitoneal (IP) Ad5/3-Δ24 in advance of a phase I clinical trial in gynecologic cancers. Syrian hamster cohorts were treated with IP Ad5/3-Δ24 or control buffer for 3 consecutive days and euthanized on study days 8, 17, 57, and 89. Blood and tissue samples were harvested from each animal. For biodistribution studies, presence and quantitation of viral levels within samples were determined via quantitative polymerase chain reaction. For safety studies, animals were assessed for adverse vector-related tissue or laboratory effects. In the biodistribution study, low levels of Ad5/3-Δ24 DNA were noted outside of the abdominal cavity. Viral DNA levels in tissues obtained from the peritoneal cavity peaked at day 8 and declined thereafter. In the safety study, no specific histopathologic changes were attributable to virus administration. Hematologic findings noted in the 1 × 10(11) viral particles (vp)/dose group on Days 4 and/or 8 were indicative of an Ad5/3-Δ24-specific generalized inflammatory response; these findings resolved by day 56. The no observable adverse effect level was determined to be 1 × 10(10) vp/dose. This study elucidates the safety profile of IP administration of the serotype chimeric infectivity-enhanced CRAd, Ad5/3-Δ24, and provides guidance for a planned phase I trial for patients with recurrent gynecologic cancers.

Vitamin E and C supplementation reduces oxidative stress, improves antioxidant enzymes and positive muscle work in chronically loaded muscles of aged rats.

Aging is associated with increased oxidative stress. Muscle levels of oxidative stress are further elevated with exercise. The purpose of this study was to determine if dietary antioxidant supplementation would improve muscle function and cellular markers of oxidative stress in response to chronic repetitive loading in aging. The dorsiflexors of the left limb of aged and young adult Fischer 344 Brown×Norway rats were loaded 3 times weekly for 4.5 weeks using 80 maximal stretch-shortening contractions per session. The contra-lateral limb served as the intra-animal control. The rats were randomly assigned to a diet supplemented with Vitamin E and Vitamin C or normal non-supplemented rat chow. Biomarkers of oxidative stress were measured in the tibialis anterior muscle. Repetitive loading exercise increased maximal isometric force, negative work and positive work in the dorsiflexors of young adult rats. Only positive work increased in the aged animals that were supplemented with Vitamin E and C. Markers of oxidative stress (H(2)O(2), total GSH, GSH/GSSG ratio, malondialdehyde and 8-OHdG) increased in the tibialis anterior muscles from aged and young adult animals with repetitive loading, but Vitamin E and C supplements attenuated this increase. MnSOD activity increased with supplementation in the young adult animals. CuZnSOD and catalase activity increased with supplementation in young adult and aged animals and GPx activity increased with exercise in the non-supplemented young adult and aged animals. The increased levels of endogenous antioxidant enzymes after Vitamin E and C supplementation appear to be regulated by post-transcriptional modifications that are affected differently by age, exercise, and supplementation. These data suggest that antioxidant supplementation improves indices of oxidative stress associated with repetitive loading exercise and aging and improves the positive work output of muscles in aged rodents.