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.

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.

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.

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.

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.

High affinity binding sites for gastrin releasing peptide on human gastric cancer and Ménétrier's mucosa.

The bombesin-like peptides gastrin releasing peptide (GRP) and neuromedin B are found in the submucosal and myenteric plexuses of the human gastrointestinal tract. These peptides are potent mitogens to Swiss 3T3 fibroblasts and are important autocrine growth factors in human small cell lung cancer cells. We have recently described the presence of receptors for the bombesin-like peptide, GRP, on the human gastric cancer cell line St42. In this study, we examined fresh resected gastric cancer and uninvolved mucosa from 23 patients for the presence of binding sites to the bombesin-like peptides. Thirteen of 23 gastric cancers expressed high affinity binding sites for bombesin (mean Kd = 3.42 nM; mean Bmax = 40.5 pmol/mg protein), of which 12 were subsequently characterized and found to be of the GRP-preferring subtype. One of 23 mucosal samples specifically bound bombesin and was the only sample from a patient with Ménétrier's disease, a disorder of mucosal growth known to be premalignant. The early gastric cancer from this patient also possessed high affinity binding sites for GRP. This is the first description of binding sites to bombesin-like peptides on human gastric cancer and Ménétrier's mucosa. The role of bombesin/GRP antagonists in the treatment of gastric cancer warrants investigation.

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.

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.

Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults.

The impact of GH on functional performance in GH-deficient adults is not well understood. To investigate the effects of GH on skeletal muscle, physical, and functional capacity, we randomized 28 GH-deficient adults to receive 3 months of recombinant human GH [rhGH: somatotropin, 6.25 microg/kg lean body mass (LBM) for 1 month, 12.5 microg/kg LBM thereafter] in a double-blind placebo-controlled crossover trial. We measured muscle fiber type, size, and insulin-like growth factor I messenger RNA, aerobic capacity [maximal oxygen uptake (VO2max), ventilation threshold (VeT)], isokinetic strength, oxygen-cost-of-walking at normal and fast speeds, and fatigue determined by the profile of mood states questionnaire. As expected, GH treatment decreased body fat, increased LBM, increased muscle fiber size, and increased muscle insulin-like growth factor-I messenger RNA 5-fold; however, muscle strength remained unchanged. At baseline, VeT occurred at a high percentage of maximal VO2max (73.3% +/-2.6) because of low VO2max (1.74+/-0.1 L/min or 20.7+/-1.3 mL/ kg x min). Walking required high oxygen consumptions representing from 83+/-4% of VeT at normal speeds to 120+/-5% of VeT at fast speeds. After rhGH, there was a significant (P = 0.03) increase in VeT (18%), compared with placebo. This was paralleled by a nonsignificant rise in VO2max. Functionally, rhGH treatment decreased the oxygen cost of walking, relative to VeT, at normal (14% decrease, P = 0.019) and fast (21% decrease, P = 0.004) SPW speeds. A 3-variable model (baseline fast SPW speed, VeT/VO2max, and VeT) accounted for 39% of the variance of change in self-reported fatigue. These data indicate that GH-deficient adults require a high fraction of VeT for daily activities, explaining the perception of increased fatigue and impaired physical performance. The actions ofrhGH on muscle fiber size translate into physiological improvement in submaximal aerobic capacity and result in functional improvement in walking ability but do not necessarily alter strength. Thus, measures of effort-independent submaximal aerobic performance provide novel objective determinants of functional impairment and fatigue and can be used to evaluate and predict response to GH treatment.

Cystic lesions of the pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke's cleft cyst, and arachnoid cyst.

The distinction among craniopharyngioma (CR), Rathke's cleft cyst (RCC), and intrasellar arachnoid cyst (AC) remains a difficult preoperative problem. Accurate diagnosis of these rare pituitary lesions is important to determine the type of treatment and predict prognostic outcome. The majority of the literature describes the clinical manifestations and management of only one of CR, RCC, or AC, rendering comparisons difficult. We conducted a study to 1) investigate distinguishing preoperative clinical, biochemical, and radiographic features of patients with CR, RCC, and AC; and 2) identify clinicopathological features that independently predict recurrence in CR and RCC in adults. Fifty-two adult patients included 21 patients with CR (mean age at initial surgery, 35 +/- 14 yr), 26 patients with RCC (mean age, 37 +/- 14 yr), and 5 patients with AC (mean age, 53 +/- 12 yr). Mean follow-up duration was 70 +/- 13 months. Patients with CR presented with hypopituitarism in 95% of cases and hyperprolactinemia in 38%. These patients also had more preoperative neurological deficits (67%), ophthalmological complaints (67%), and significantly higher psychiatric manifestations (33%; P = 0.003) than those with RCC or AC. Patients with AC presented with headaches (60%), visual field deficits (60%), or impotence (50%) in the absence of other specific endocrine dysfunction symptoms. Using biochemical criteria, the percentage of patients with two or more pituitary hormonal axes impaired preoperatively was 67% for CR and 62% for RCC, significantly greater (P = 0.03) than that for the AC patients who had pituitary dysfunction of only one axis. The composition of CR lesions was cystic (38%), solid (10%), or mixed solid and cystic (43%). Patients with RCC or AC groups had a significantly greater proportion (P = 0.006) of purely cystic lesions (88% and 100%, respectively). Calcification detectable on computed tomographic scanning was present in 87% of patients with CR, a significantly greater proportion (P < 0.001) compared to those with RCC (13%) or AC (0%). No significant differences were found between the groups based on computed tomography density, the presence of postcontrast enhancement, or magnetic resonance imaging. Recurrence rate was 62% for CR, 19% for RCC, and 20% for AC. Surgical intervention statistically improved most neurological, ophthalmological, and psychiatric manifestations; in contrast, galactorrhea, menstrual dysfunction, and diabetes insipidus (52% CR; 31% RCC) did not improve or became worse postoperatively. A significantly higher percentage of patients with CR required postoperative hormone replacement. Similarly, there was a biochemical trend suggesting that a smaller proportion of patients with CR improved in at least one pituitary axis after surgery (P = 0.08) compared to those with RCC or AC. There was a positive correlation between cyst size and recurrence rate (r = 0.689; P < 0.01) and between cyst size and time to recurrence (r = 0.582; P = 0.037) for all three groups. We describe the largest clinical, biochemical, radiographic, and histological series of adult patients with cystic disease of the sella turcica. Patients with AC tended to be older at initial diagnosis than CR or RCC patients. Mass effects, such as visual problems and headaches, are common symptoms of all three cystic lesions, but psychiatric deficits favor a diagnosis of CR. Calcification or solid components on neuroimaging characterize CR. Endocrinological deficits, especially diabetes insipidus, had the worst prognosis after surgery. Low recurrence rates can be expected for RCC and AC. These data have direct implications for the management and monitoring of patients with cystic lesions of the sella turcica.

Comparison of estimates of zinc absorption in humans by using 4 stable isotopic tracer methods and compartmental analysis.

BACKGROUND: Adjustment of gastrointestinal absorption is the primary means of maintaining zinc homeostasis; however, a precise, accurate method for measuring zinc absorption in humans has not been identified. OBJECTIVE: The purpose of this study was to compare the estimates of the fraction of dietary zinc absorbed (FZA) by using 4 stable isotopic tracer methods: mass balance (MB) corrected for endogenous secretion, fecal monitoring (FM), deconvolution analysis (DA), and the double isotopic tracer ratio (DITR) method. DESIGN: All 4 methods were applied to a single data set for each of 6 women. FZA was also determined for each subject by using a detailed compartmental model of zinc metabolism, and that value was used as the reference with which the simpler methods were compared. RESULTS: The estimates of FZA (&xmacr; +/- SD) determined by DA (0.27 +/- 0. 08) and the DITR technique in plasma (0.30 +/- 0.10), 24-h urine samples (0.29 +/- 0.09), and spot urine samples (0.291 +/- 0.089) all compared well with the FZA reference value from the compartmental model (0.30 +/- 0.10). The MB and FM methods tended to overestimate FZA compared with the reference value. CONCLUSIONS: The determination of FZA by MB or FM is laborious, is sensitive to subject compliance, and may result in an overestimate. DA, although relatively accurate, has the disadvantage of requiring multiple blood drawings over several days. In contrast, the DITR technique applied to a spot urine specimen obtained >/=3 d after tracer administration provides an accurate measure of FZA and is easy to implement; therefore, it is the recommended method for determination of FZA.

Zinc absorption in women during pregnancy and lactation: a longitudinal study.

Zinc is essential for normal fetal growth and development and for milk production during lactation. The metabolic adjustments made in zinc utilization to meet these needs have not been described. The purpose of this study was to determine whether fractional zinc absorption (FZA) is altered during pregnancy and lactation and, if so, to determine whether the change is related to maternal zinc status, specifically, concentrations of zinc in plasma, erythrocytes, urine, and breast milk and dietary zinc intake. Thirteen women were studied at five time points: once preconception; at 8-10, 24-26, and 34-36 wk gestation; and once while they were lactating 7-9 wk postpartum. Zinc intake increased by 35 mumol/d (2.3 mg/d) from preconception to 34-36 wk (P = 0.04); it tended to decrease (P > 0.05) during lactation but did not return to the preconception level. The amount of zinc in breast milk averaged 2.0 mg/d at the lactation time point. FZA measured from urinary enrichments of two stable isotopes of zinc increased from 14% preconception to 25% during lactation (P = 0.023) but the increase to 19% at 34-36 wk gestation was not significant. No increase in FZA occurred in four women who took iron supplements during lactation. FZA was negatively correlated with plasma zinc concentration at 34-36 wk gestation and with urinary zinc excretion at all time points. The nearly twofold increase in zinc absorption during lactation was presumably in response to the demand for zinc to synthesize breast milk.

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.

A compartmental model of zinc metabolism in healthy women using oral and intravenous stable isotope tracers.

A mathematical model of zinc metabolism in six healthy women (average age: 30 +/- 11 y) was developed by using stable isotopes of zinc. After equilibration on a constant diet containing 7.0 mg Zn/d, an oral tracer highly enriched in 67Zn and an intravenous tracer highly enriched in 70Zn were administered simultaneously. Multiple plasma and 24-h urine samples were collected for the next 7 d with complete fecal collections for 11 d. Tracer-trace ratios in plasma, urine, and feces were calculated from isotope ratios of 67Zn to 66Zn and 70Zn to 66Zn measured by using inductively coupled plasma-mass spectrometry. An a priori identifiable model composed of seven compartments was developed to describe the kinetics of both tracers as well as that of naturally occurring zinc. The parameters of the model were fitted to the data by using the SAAM-CONSAM modeling software and were estimated with good precision. Several important, not directly measurable zinc variables were estimated (mean +/- SEM) from the model including the fractional absorption from the gastrointestinal tract (0.279 +/- 0.043), the rates of endogenous secretion (2.79 +/- 0.49 mg/d) and excretion (2.01 +/- 0.35 mg/d), the fractional turnover rate of the plasma pool (131 +/- 20/d), and the sizes (7.2 +/- 1.2 and 77.1 +/- 6.4 mg) and fractional turnover rates (22.3 +/- 7.1 and 1.49 +/- 0.18/d) of the fast and slow tissue pools equilibrating with the plasma, respectively.

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.

Interleukin-10. A role in the development of postoperative immunosuppression.

BACKGROUND: The cause of diminished monocyte major histocompatibility complex class II antigen expression after surgery or trauma is unclear. Interleukin-10 (IL-10) regulates inflammatory cytokine production and major histocompatibility complex class II (HLA-DR) expression in vitro. OBJECTIVES: To quantify in vivo IL-10 messenger RNA (mRNA) and protein and monocyte HLA-DR expression after major surgery and to investigate the effects of IL-10 neutralizing blockade on monocyte HLA-DR expression in vitro. DESIGN: Inception cohort study of 48 surgical patients from preoperative status to postoperative day 7 and 9 healthy volunteers (controls). SETTING: Large teaching hospital, Northern England. PATIENTS: Monocyte HLA-DR and cytokine mRNA expression was determined in 32 of 48 consecutive patients undergoing elective major resectional surgery. Mononuclear cells for in vitro studies and serum samples for IL-10 measurement were obtained from the remaining 16 patients. MAIN OUTCOME MEASURES: Monocyte HLA-DR expression determined by flow cytometry, IL-10, and tumor necrosis factor mRNA in peripheral blood mononuclear cells assayed by multiplex reverse transcriptase polymerase chain reaction, and serum IL-10 determined by enzyme-linked immunosorbent assay. RESULTS: Monocyte HLA-DR expression (in mean channel fluorescence units [MCF]) was significantly reduced 24 hours after surgery (MCF [+/- SEM], 32.6 +/- 2.3 vs 16.3 +/- 1.2; P < .001) and remained low during the first postoperative week. A relative increase in IL-10 to G3PDH mRNA ratio (mean [+/- SEM], 0.95 +/- 0.08 vs 0.59 +/- 0.06; P < .01) and serum IL-10 (mean [+/- SEM], 18.1 +/- 4.1 vs 5.4 +/- 0.8 pg/mL; P < .01) was noted on the first postoperative day. A significant correlation existed between HLA-DR antigen expression and the presence of IL-10 mRNA transcript on the first postoperative day (P < .01). Lipopolysaccharide-induced up-regulation of monocyte HLA-DR expression was significantly impaired on the first postoperative day (mean [+/- SEM], 151% +/- 24.4% vs 60% +/- 10.1%; P < .01), but this was partially reversed by IL-10 neutralizing antibody (mean [+/- SEM], 60% +/- 10.1% vs 115% +/- 11.6%; P < .01). CONCLUSIONS: Interleukin-10 gene expression correlates with the fall in monocyte HLA-DR antigen expression in patients undergoing major abdominal surgery and may account for the immunosuppression associated with surgical injury.

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.

The relationship between plasma pharmacokinetics and tissue metabolites of 5-fluorouracil (5-FU) in patients with colorectal cancer.

To assess the relationship between the plasma pharmacokinetics of 5-Fluorouracil (5-FU) and the levels of intracellular 5-FU metabolites, we have studied eight patients presenting with primary carcinomas of the colon and rectum. Serum 5-FU levels and fluorinated metabolites within normal and malignant tissue were estimated using chromatographic methods. An analysis of the total fluorinated products against plasma halflife, plasma clearance and maximum plasma concentration failed to demonstrate any significant correlation. Furthermore the differing levels of 5-FU metabolites in normal and malignant tissue could not be correlated with the pharmacokinetic parameters studied. It is concluded that the cellular levels of active 5-FU metabolites reflect local cellular activity rather than the handling of the drug in vivo.