Advanced practice physiotherapy care in emergency departments for patients with musculoskeletal disorders: a pragmatic cluster randomized controlled trial and cost analysis.

BACKGROUND: Advanced practice physiotherapy (APP) models of care where physiotherapists are primary contact emergency department (ED) providers are promising models of care to improve access, alleviate physicians' burden, and offer efficient centered patient care for patients with minor musculoskeletal disorders (MSKD). OBJECTIVES: To compare the effectiveness of an advanced practice physiotherapist (APPT)-led model of care with usual ED physician care for persons presenting with a minor MSKD, in terms of patient-related outcomes, health care resources utilization, and health care costs. METHODS: This trial is a multicenter stepped-wedge cluster randomized controlled trial (RCT) with a cost analysis. Six Canadian EDs (clusters) will be randomized to a treatment sequence where patients will either be managed by an ED APPT or receive usual ED physician care. Seven hundred forty-four adults with a minor MSKD will be recruited. The main outcome measure will be the Brief Pain Inventory Questionnaire. Secondary measures will include validated self-reported disability questionnaires, the EQ-5D-5L, and other health care utilization outcomes such as prescription of imaging tests and medication. Adverse events and re-visits to the ED for the same complaint will also be monitored. Health care costs will be measured from the perspective of the public health care system using time-driven activity-based costing. Outcomes will be collected at inclusion, at ED discharge, and at 4, 12, and 26 weeks following the initial ED visit. Per-protocol and intention-to-treat analyses will be performed using linear mixed models with a random effect for cluster and fixed effect for time. DISCUSSION: MSKD have a significant impact on health care systems. By providing innovative efficient pathways to access care, APP models of care could help relieve pressure in EDs while providing efficient care for adults with MSKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05545917 . Registered on September 19, 2022.

Are medical comorbidities contributing to the use of opioid analgesics in patients with knee osteoarthritis?

BACKGROUND: Although opioid analgesics are not generally recommended for treatment of knee osteoarthritis (OA), they are frequently used. We sought to determine the association between medical comorbidities and self-reported opioid analgesic use in these patients. METHODS: This cross-sectional study recruited patients referred to two provincial hip and knee clinics in Alberta, Canada for consideration of total knee arthroplasty. Standardized questionnaires assessed demographic (age, gender, income, education, social support, smoking status) and clinical (pain, function, total number of troublesome joints) characteristics, comorbid medical conditions, and non-surgical OA management participants had ever used or were currently using. Multivariable Poisson regression with robust estimate of the standard errors assessed the association between comorbid medical conditions and current opioid use, controlling for potential confounders. RESULTS: 2,127 patients were included: mean age 65.4 (SD 9.1) years and 59.2% female. Currently used treatments for knee OA were: 57.6% exercise and/or physiotherapy, 61.1% NSAIDs, and 29.8% opioid analgesics. In multivariable regression, controlling for potential confounders, comorbid hypertension (RR 1.18, 95% CI 1.02-1.37), gastrointestinal disease (RR 1.31, 95% CI 1.07-1.60), depressed mood (RR 1.25, 95% CI 1.05-1.48) and a higher number of troublesome joints (RR 1.04 per joint, 95% CI 1.00-1.09) were associated with opioid use, with no association found with having ever used recommended non-opioid pharmacological or non-pharmacological treatments. CONCLUSIONS: In a large cohort of patients with knee OA, of 12 comorbidities assessed, comorbid hypertension, gastrointestinal disease, and depressed mood were associated with current use of opioid analgesics, in addition to total burden of troublesome joints. Improved guidance on the management of painful OA in the setting of common comorbidities is warranted.

Clinically Meaningful Change for Physical Performance: Perspectives of the ICFSR Task Force.

For clinical studies of sarcopenia and frailty, clinically meaningful outcome measures are needed to monitor disease progression, evaluate efficacy of interventions, and plan clinical trials. Physical performance measures including measures of gait speed and other aspects of mobility and strength have been used in many studies, although a definition of clinically meaningful change in performance has remained unclear. The International Conference on Frailty and Sarcopenia Research Task Force (ICFSR-TF), a group of academic and industry scientists investigating frailty and sarcopenia, met in Miami Beach, Florida, USA in February 2019 to explore approaches for establishing clinical meaningfulness in a manner aligned with regulatory authorities. They concluded that clinical meaningful change is contextually dependent, and that both anchor- based and distribution-based methods of quantifying physical function are informative and should be evaluated relative to patient-reported outcomes. In addition, they identified additional research needed to enable setting criteria for clinical meaningful change in trials.

Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management.

OBJECTIVE: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. METHODS: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

Prevalence of sarcopenic obesity in adults with end-stage knee osteoarthritis.

OBJECTIVE: To identify the prevalence of sarcopenic obesity, a phenotype of low muscle mass and high adiposity, in adults with end-stage knee osteoarthritis (OA). Various diagnostic criteria, including assessment of muscle/fat mass, muscle strength and physical function, were used to identify patients with and without sarcopenic obesity, and to compare outcomes of pain, function and quality of life. DESIGN: Cross-sectional clinical study including adults with a body mass index (BMI) ≥30 kg/m2 and knee OA. Body composition was measured by dual-energy X-ray absorptiometry (DXA). Assessments included gait speed, handgrip strength, six minute walk test, and self-reported pain, physical function, and health-related quality of life using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and EuroQol Foundation (EQ-5D). RESULTS: 151 adults (59% female) aged 65.1 ± 7.9 years, mean BMI 37.1 ± 5.5 kg/m2, were included. Prevalence of sarcopenic obesity using diagnostic cut-offs of appendicular skeletal muscle mass (ASM) relevant to height2, weight and BMI varied from 1.3% (95% confidence interval (CI): 0.2-4.7%) to 14.6% (9.4-21.2%) and 27.2% (20.2-35%), respectively. A combined diagnostic approach including low ASM with either low strength or low function yielded a prevalence of 8.6% (4.7-14.3%). Sarcopenic obesity influenced walking speed, endurance, strength, and patient-reported difficulty with self-care activities, regardless of diagnostic approach. CONCLUSION: Prevalence of sarcopenic obesity varied depending on diagnostic criteria. Given the impact of this condition and OA on physical function, we suggest a combined diagnostic approach be used to clarify expected prevalence and enable early clinical identification and management of sarcopenic obesity in patients with knee OA.

Can effusion-synovitis measured on ultrasound or MRI predict response to intra-articular steroid injection in hip osteoarthritis?

OBJECTIVES: Intra-articular steroid injection (IASI) is an effective therapy for hip osteoarthritis (OA), but carries risks and provides significant pain relief to only two thirds of patients. We attempted to predict response to IASI in hip OA patients using baseline clinical, ultrasound, and MRI data. METHODS: Observational study of 97 subjects with symptomatic hip OA presenting for IASI. At baseline and 8 weeks we obtained hip MRI, grayscale and Doppler ultrasound, clinical range of motion (ROM), timed-up and go test (TUG) scores, and self-reported Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain, stiffness, and function scores. Bone-capsule distance (BCD) measurements of inflammation on hip ultrasound and MRI were measured at three locations: the proximal-most uncovered portion of the femoral head, the superficial-most (apex) portion of the femoral head, and the largest fluid pocket at the femoral neck. RESULTS: Ultrasound and MRI BCD correlated with each other significantly and strongly at the apex and neck. Power Doppler findings did not correlate significantly with any other imaging indices. Eight weeks post-injection, WOMAC pain, function, and stiffness scores significantly improved and TUG time improved nearly to the level of significance, but there were no significant changes in ultrasound, MRI, or Doppler indices. Baseline variables were not significantly different between responder and nonresponder WOMAC pain or TUG time cohorts. CONCLUSION: Basic measures of inflammation on ultrasound and MRI are highly related to each other, but provide little insight into patient function and pain after IASI. Other mechanisms to explain improvement in patient status after IASI are likely at work.

A Phase 2 Randomized Study Investigating the Efficacy and Safety of Myostatin Antibody LY2495655 versus Placebo in Patients Undergoing Elective Total Hip Arthroplasty.

BACKGROUND: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. OBJECTIVES: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. DESIGN: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period. SETTING: Forty-two sites in 11 countries. PARTICIPANTS: Individuals (N=400) aged ≥50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 ± 6 days after randomization. INTERVENTION: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24. MEASUREMENTS: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time. RESULTS: Participants: 59% women, aged 69 ± 8 years, BMI 29 ± 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected. CONCLUSION: Dose-dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective.

Outcomes associated with early post-traumatic osteoarthritis and other negative health consequences 3-10 years following knee joint injury in youth sport.

OBJECTIVE: Post-traumatic osteoarthritis (PTOA) commonly affects the knee joint. Although the risk of PTOA substantially increases post-joint injury, there is little research examining PTOA outcomes early in the period between joint injury and disease onset. Improved understanding of this interval would inform secondary prevention strategies aimed at preventing and/or delaying PTOA progression. This study examines the association between sport-related knee injury and outcomes related to development of PTOA, 3-10 years post-injury. DESIGN: This preliminary analysis of the first year of a historical cohort study includes 100 (15-26 years) individuals. Fifty with a sport-related intra-articular knee injury sustained 3-10 years previously and 50 uninjured age, sex and sport matched controls. The primary outcome was the 'Symptoms' sub-scale of the Knee Osteoarthritis and Injury Outcome Score (KOOS). Secondary outcomes included; the remaining KOOS subscales, body mass index (BMI), hip abductor/adductor and knee extensor/flexor strength, estimated aerobic capacity (VO2max) and performance scores on three dynamic balance tests. Descriptive statistics (mean within-pair difference; 95% Confidence interval (CI) and conditional odds ratio (OR, 95% CI; BMI) were used to compare study groups. RESULTS: Injured participants demonstrated poorer KOOS outcomes [symptoms -9.4 (-13.6, -5.2), pain -4.0 (-6.8, -1.2), quality-of-life -8.0 (-11.0, -5.1), daily living -3.0 (-5.0, -1.1) and sport/recreation -6.9 (-9.9, -3.8)], were 3.75 times (95% CI 1.24, 11.3) more likely to be overweight/obese and had lower triple single leg hop scores compared to controls. No significant group differences existed for remaining balance scores, estimated VO2max, hip or knee strength ratios or side-to-side difference in hip abductor/adductor or quadricep/hamstring strength. CONCLUSIONS: This study provides preliminary evidence that youth/young adults following sport-related knee injury report more symptoms and poorer function, and are at greater risk of being overweight/obese 3-10 years post-injury compared to matched uninjured controls.

Measurement properties of the WOMAC LK 3.1 pain scale.

OBJECTIVE: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is applied extensively to patients with osteoarthritis of the hip or knee. Previous work has challenged the validity of its physical function scale however an extensive evaluation of its pain scale has not been reported. Our purpose was to estimate internal consistency, factorial validity, test-retest reliability, and the standard error of measurement (SEM) of the WOMAC LK 3.1 pain scale. METHOD: Four hundred and seventy-four patients with osteoarthritis of the hip or knee awaiting arthroplasty were administered the WOMAC. Estimates of internal consistency (coefficient alpha), factorial validity (confirmatory factor analysis), and the SEM based on internal consistency (SEM(IC)) were obtained. Test-retest reliability [Type 2,1 intraclass correlation coefficients (ICC)] and a corresponding SEM(TRT) were estimated on a subsample of 36 patients. RESULTS: Our estimates were: internal consistency alpha=0.84; SEM(IC)=1.48; Type 2,1 ICC=0.77; SEM(TRT)=1.69. Confirmatory factor analysis failed to support a single factor structure of the pain scale with uncorrelated error terms. Two comparable models provided excellent fit: (1) a model with correlated error terms between the walking and stairs items, and between night and sit items (chi2=0.18, P=0.98); (2) a two factor model with walking and stairs items loading on one factor, night and sit items loading on a second factor, and the standing item loading on both factors (chi2=0.18, P=0.98). CONCLUSION: Our examination of the factorial structure of the WOMAC pain scale failed to support a single factor and internal consistency analysis yielded a coefficient less than optimal for individual patient use. An alternate strategy to summing the five-item responses when considering individual patient application would be to interpret item responses separately or to sum only those items which display homogeneity.

Effects of testosterone replacement in human immunodeficiency virus-infected women with weight loss.

The objective of this study was to determine whether physiological testosterone replacement increases fat-free mass (FFM) and muscle strength and contributes to weight maintenance in HIV-infected women with relative androgen deficiency and weight loss. Fifty-two HIV-infected, medically stable women, 18-50 yr of age, with more than 5% weight loss over 6 months and testosterone levels below 33 ng/dl were randomized into this double-blind, placebo-controlled trial of 24-wk duration. Subjects in the testosterone group applied testosterone patches twice weekly to achieve a nominal delivery of 300 mug testosterone over 24 h. Data were evaluable for 44 women. Serum average total and peak testosterone levels increased significantly in the testosterone group, but did not change in the placebo group. However, there were no significant changes in FFM (testosterone, 0.7 +/- 0.4 kg; placebo, 0.3 +/- 0.4 kg), fat mass (testosterone, 0.3 +/- 0.7 kg; placebo, 0.6 +/- 0.7 kg), or body weight (testosterone, 1.0 +/- 0.9 kg; placebo, 0.9 +/- 0.8 kg) between the two treatment groups. There were no significant changes in leg press strength, leg power, or muscle fatigability in either group. Changes in quality of life, sexual function, cognitive function, and Karnofsky performance scores did not differ significantly between the two groups. High-density lipoprotein cholesterol levels decreased significantly in the testosterone group. The patches were well tolerated. We conclude that physiological testosterone replacement was safe and effective in raising testosterone levels into the mid to high normal range, but did not significantly increase FFM, body weight, or muscle performance in HIV-infected women with low testosterone levels and mild weight loss. Additional studies are needed to fully explore the role of androgens in the regulation of body composition in women.

Peroxyacetyl nitrate and peroxypropionyl nitrate during SCOS 97-NARSTO.

Peroxyacyl nitrates [RC(O)OONO2] play an important role in urban air quality and tropospheric chemistry. They also receive attention as mutagens, phytotoxins, and possible air quality indicators of changes in vehicle fuel composition. Ambient concentrations of PAN (R = CH3) and PPN (R = C2H5) have been measured during summer 1997 at two southern California locations, Azusa (July 14-October 16) and Simi Valley (June 18-October 16). The highest concentrations were 4.8 ppb for PAN and 0.72 ppb for PPN in Azusa and 3.0 ppb for PAN and 0.28 ppb for PPN in Simi Valley. Ambient levels of PAN and PPN during summer 1997 were lower than those measured in the last three studies carried out in southern California in the summers of 1990, 1991, and 1993. Average PPN/PAN concentration ratios were about the same in Azusa (0.142+/-0.025, n = 132) and in Simi Valley (0.135+/-0.028, n = 138). The PPN/PAN ratio measured in Azusa was the same as that measured at that location in 1993 prior to the introduction in 1996 of California Phase 2 reformulated gasoline. Diurnal variations of PAN and PPN generally followed those of ozone with respect to time of day but not with respect to amplitude. The PAN/ozone ratio was lower in Simi Valley than in Azusa, and daytime minima were recorded at both locations. The amount of PAN lost by thermal decomposition accounted for large fractions of the amount of PAN formed (measured + decomposed) during daytime hours at both locations. The amount of PAN lost by thermal decomposition was higher in Azusa and was up to ca. 8.5 ppb, i.e., 4-5 times more than that measured, when afternoon temperatures were ca. 40 degrees C.

Testosterone dose-response relationships in healthy young men.

Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18-35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk. Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose. We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.

Exchangeable zinc pool masses and turnover are maintained in healthy men with low zinc intakes.

Previous studies suggest that rapidly exchanging zinc pools (EZP), thought to supply the zinc required by tissues, are smaller and turn over more rapidly in individuals with lower zinc intakes. We studied the effects of low dietary zinc (4.6 mg/d) on EZP mass and turnover in seven healthy men confined during a 20-wk clinical study. Supplements of 9.1 mg zinc were given during the 5-wk baseline and repletion periods, and placebos were given during a 10-wk zinc-restriction period. Stable 70Zn tracers were administered intravenously at the end of baseline, 3 and 10 wk after the start of zinc restriction and at the end of repletion. Multiple plasma samples were collected over an 8-d period after tracer administration. 70Zn:66Zn ratios were measured using inductively coupled plasma mass spectrometry, and tracer-tracee data were analyzed by compartmental modeling. Activities of the zinc-dependent enzymes, alkaline phosphatase and 5'nucleotidase, were unchanged during the study. There were no significant changes in EZP masses or kinetic parameters. A three-compartment model indicated that the masses of plasma zinc and total EZP averaged 3.25 +/- 0.58 and 147.8 +/- 33.2 mg, respectively, at the four time points studied. Plasma zinc mass turned over at an average of 5.3 times per hour. There was an 11% reduction (P = 0.06) in plasma zinc flux 3 wk after the start of the low zinc diet period, but it returned to baseline values after 10 wk of zinc restriction. The results suggest that total EZP mass is maintained when dietary zinc is reduced to 4.6 mg/d over a 10-wk period.

Tobacco policy and the role of law enforcement in prevention: the value of understanding context.

The Florida Office of Tobacco Control sponsors evaluations of the effect of its comprehensive youth tobacco prevention initiatives. As part of this evaluation, a quasi-experiment designed to assess the effect of law enforcement on youth tobacco use was conducted. An in-depth qualitative study was a critical component of this research. This study provided a rich description of the context in which law enforcement was implemented. Data collection involved interviews with judges, clerks of court, and selected officials in each of the study counties. Approximately 70 interviews were conducted. Extensive, ongoing computer-assisted analysis complemented the process. Several consistent themes emerged during the research that helped to give contextual meaning to the findings. These themes provided critical insights into the complexity of policies about youth tobacco possession, and the findings helped illuminate the varying contexts in which these interventions were applied.

Effect of acute zinc depletion on zinc homeostasis and plasma zinc kinetics in men.

BACKGROUND: Zinc homeostasis and normal plasma zinc concentrations are maintained over a wide range of intakes. OBJECTIVE: The objective was to identify the homeostatic response to severe zinc depletion by using compartmental analysis. DESIGN: Stable zinc isotope tracers were administered intravenously to 5 men at baseline (12.2 mg dietary Zn/d) and after 5 wk of acute zinc depletion (0.23 mg/d). Compartmental modeling of zinc metabolism was performed by using tracer and mass data in plasma, urine, and feces collected over 6-14 d. RESULTS: The plasma zinc concentration fell 65% on average after 5 wk of zinc depletion. The model predicted that fractional zinc absorption increased from 26% to essentially 100%. The rate constants for zinc excretion in the urine and gastrointestinal tract decreased 96% and 74%, respectively. The rate constants describing the distribution kinetics of plasma zinc did not change significantly. When zinc depletion was simulated by using an average mass model of zinc metabolism at baseline, the only change that accounted for the observed fall in plasma zinc concentration was a 60% reduction in the rate constant for zinc release from the most slowly turning over zinc pool. The large changes in zinc intake, excretion, and absorption-even when considered together-only explained modest reductions in plasma zinc mass. CONCLUSION: The kinetic analysis with a compartmental model suggests that the profound decrease in plasma zinc concentrations after 5 wk of severe zinc depletion was mainly due to a decrease in the rate of zinc release from the most slowly turning over body zinc pool.

Accuracy of simple techniques for estimating fractional zinc absorption in humans.

The theoretical basis of the accuracy of a number of simple techniques for estimating fractional zinc absorption (FZA) in humans using stable isotopic tracers has not been evaluated. These techniques include fecal monitoring (FM), deconvolution analysis (DA), double isotopic tracer ratio (DITR) and indicator dilution methods. Using a compartmental model, we investigated the accuracy and logic of each of these techniques. Time-dependent estimates of FZA based on the simple techniques were simulated using the compartmental model and compared with the known FZA derived from the model. The analysis elucidated logical errors in some of the FM techniques, and even when these problems were corrected, the FM technique was still prone to errors due to incomplete fecal tracer recovery and variable gastrointestinal (GI) transit time. Although logically correct, the indicator dilution techniques were also highly sensitive to incomplete fecal tracer recovery and variable GI transit time. The DA and DITR techniques were the most robust in that they were logically correct and were insensitive to incomplete fecal tracer recovery and variable GI transit time. Although all of the DA and DITR methods provided similarly good estimates of FZA relative to the compartmental model, the DITR technique performed on a spot urine specimen obtained several days after tracer administration was the preferred choice because of its simplicity and minimal requirements for patient compliance.

Proof of the effect of testosterone on skeletal muscle.

In spite of the widespread abuse of androgenic steroids by athletes and recreational body-builders, the effects of these agents on athletic performance and physical function remain poorly understood. Experimentally induced androgen deficiency is associated with a loss of fat-free mass; conversely, physiologic testosterone replacement of healthy, androgen-deficient men increases fat-free mass and muscle protein synthesis. Testosterone supplementation of HIV-infected men with low testosterone levels and of older men with normally low testosterone concentrations also increases muscle mass. However, we do not know whether physiologic testosterone replacement can improve physical function and health-related quality of life, and reduce the risk of falls and disability in older men or those with chronic illness. Testosterone increases maximal voluntary strength in a dose-dependent manner and thus might improve performance in power-lifting events. However, testosterone has not been shown to improve performance in endurance events. The mechanisms by which testosterone increases muscle mass are not known, but probably involve alterations in the expression of multiple muscle growth regulators.

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects < or =40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

Choosing a route of administration for quadrivalent meningococcal polysaccharide vaccine: intramuscular versus subcutaneous.

A clinical trial was conducted to compare intramuscular (im) with subcutaneous (sc) routes for administration of quadrivalent meningococcal polysaccharide vaccine in 141 adults. Safety assessment showed the im route had reduced erythema (P<.01) and reduced headache on days 1 and 2 (P<.05). Serological testing for serum bactericidal antibody titers against capsular groups A and C did not detect significant differences.

The detection and quantitation of inflammation in the central nervous system during experimental allergic encephalomyelitis using the radiopharmaceutical 99mTc-RP128.

RP128 is a novel agent which readily chelates 99mTc to form a radiopharmaceutical which binds in vivo to the tuftsin receptor located specifically on neutrophils and monocyte-macrophages, therefore removing the need for in vitro cell labelling prior to intravenous administration. We have assessed the ability of 99mTc-RP128 to detect central nervous system (CNS) inflammation in experimental allergic encephalomyelitis (EAE), an animal model of the human disease multiple sclerosis. The radiopharmaceutical was recorded at significantly increased levels in all EAE diseased CNS tissues, compared to normal and control samples, at 0.5, 1 and 3 h post-injection using a dual radioisotope technique to correct for non-extravasated tracer (P<0.05). Moreover, extravascular accumulation of the agent could be clearly demonstrated in inflammatory tissues with minimal loss of sensitivity when the secondary isotopic correction for blood volume was omitted. In addition, 99mTc-RP128 successfully monitored glucocorticoid suppression of inflammation (P<0.05), recording a typical dose-response to increasing steroid concentration. Clearly, 99mTc-RP128 can quantitatively detect CNS inflammation and assess responses to therapy indicating potential value as an imaging agent both clinically and as a research aid. Furthermore, the rapid in vivo labelling by 99mTc-RP128 of specific inflammatory cells combined with the ability to monitor the progress of anti-inflammatory therapeutics may recommend the agent for use in a variety of inflammatory conditions.