Pamela Wolfe

The Effect of Lopinavir/Ritonavir on the Renal Clearance of Tenofovir in HIV‐infected Patients

We determined the effects of lopinavir/ritonavir on tenofovir renal clearance. Human immunodeficiency virus‐infected subjects taking tenofovir disoproxil fumarate (TDF) were matched on age, race, and gender and were enrolled into one of the following two groups: group 1: subjects taking TDF plus lopinavir/ritonavir plus other nucleoside reverse transcriptase inhibitors (NRTIs); group 2: subjects taking TDF plus NRTIs and/or non‐NRTIs but no protease inhibitors. Twenty‐four‐hour blood and urine collections were carried out in subjects for tenofovir quantification. Drug transporter genotype associations with tenofovir pharmacokinetics were examined. In 30 subjects, median (range) tenofovir apparent oral clearance, renal clearance, and fraction excreted in urine were 34.6 l/h (20.6–89.5), 11.3 l/h (6.2–22.6), and 0.33 (0.23–0.5), respectively. After adjusting for renal function, tenofovir renal clearance was 17.5% slower (P=0.04) in subjects taking lopinavir/ritonavir versus those not taking a protease inhibitor, consistent with a renal interaction between these drugs. Future studies should clarify the exact mechanism and whether there is an increased risk of nephrotoxicity.

Sources and sinks of formaldehyde and acetaldehyde : An analysis of Denver's ambient concentration data

Four-hour average concentration data for formaldehyde and acetaldehyde have been collected in downtown Denver for each winter since December 1987, and on a year-round basis since October 1991. Carbon monoxide measurements have also been made at the same site since October 1991. These data have been analyzed in an attempt to identify the important sources and sinks for these carbonyl compounds in downtown Denver. We have found that motor vehicle emissions are a major source of these compounds all year. Although we do not find evidence for significant net photochemical production, we do find evidence for photochemical sources and sinks of both compounds. We have applied statistical techniques to ambient concentration data that can extract useful information about these atmospheric sources, sinks and processes, in spite of the large day-to-day variability in the data. Formaldehyde concentrations were found to have increased significantly during three recent winters when at least 2.6% oxygen-content fuel was required compared to two earlier winters when at least 2.0% oxygen-content fuel was required. The increase in formaldehyde concentration coincides with the increase in oxygenate content required in the fuel, but may be due to other causes.

Early Neuromuscular Electrical Stimulation to Improve Quadriceps Muscle Strength After Total Knee Arthroplasty: A Randomized Controlled Trial

Background The recovery of quadriceps muscle force and function after total knee arthroplasty (TKA) is suboptimal, which predisposes patients to disability with increasing age. Objective The purpose of this investigation was to evaluate the efficacy of quadriceps muscle neuromuscular electrical stimulation (NMES), initiated 48 hours after TKA, as an adjunct to standard rehabilitation. Design This was a prospective, longitudinal randomized controlled trial. Methods Sixty-six patients, aged 50 to 85 years and planning a primary unilateral TKA, were randomly assigned to receive either standard rehabilitation (control) or standard rehabilitation plus NMES applied to the quadriceps muscle (initiated 48 hours after surgery). The NMES was applied twice per day at the maximum tolerable intensity for 15 contractions. Data for muscle strength, functional performance, and self-report measures were obtained before surgery and 3.5, 6.5, 13, 26, and 52 weeks after TKA. Results At 3.5 weeks after TKA, significant improvements with NMES were found for quadriceps and hamstring muscle strength, functional performance, and knee extension active range of motion. At 52 weeks, the differences between groups were attenuated, but improvements with NMES were still significant for quadriceps and hamstring muscle strength, functional performance, and some self-report measures. Limitations Treatment volume was not matched for both study arms; NMES was added to the standard of care treatment. Furthermore, testers were not blinded during testing, but used standardized scripts to avoid bias. Finally, some patients reached the maximum stimulator output during at least one treatment session and may have tolerated more stimulation. Conclusions The early addition of NMES effectively attenuated loss of quadriceps muscle strength and improved functional performance following TKA. The effects were most pronounced and clinically meaningful within the first month after surgery, but persisted through 1 year after surgery.

Drug/Drug Interaction Between Lopinavir/Ritonavir and Rosuvastatin in Healthy Volunteers

Objectives:This open-label, single-arm, pharmacokinetic (PK) study in HIV-seronegative volunteers evaluated the bioequivalence of rosuvastatin and lopinavir/ritonavir when administered alone and in combination. Tolerability and lipid changes were also assessed. Methods:Subjects took 20 mg of rosuvastatin alone for 7 days, then lopinavir/ritonavir alone for 10 days, and then the combination for 7 days. Intensive PK sampling was performed on days 7, 17, and 24. Results:Twenty subjects enrolled, and PK data were available for 15 subjects. Geometric mean (±SD) rosuvastatin area under the concentration time curve (AUC)[0,τ] and maximum concentration (Cmax) were 47.6 ng·h/mL (±15.3) and 4.34 ng/mL (±1.8), respectively, when given alone versus 98.8 ng·h/mL (±65.5) and 20.2 ng/mL (±16.9) when combined with lopinavir/ritonavir (P < 0.0001). The geometric mean ratio was 2.1 (90% confidence interval [CI]: 1.7 to 2.6) for rosuvastatin AUC[0,τ] and 4.7 (90% CI: 3.4 to 6.4) for rosuvastatin Cmax with lopinavir/ritonavir versus rosuvastatin alone (P < 0.0001). There was 1 asymptomatic creatine phosphokinase elevation 17 times the upper limit of normal (ULN) and 1 liver function test elevation between 1.1 and 2.5 times the ULN with the combination. Conclusions:Rosuvastatin low-density lipoprotein reduction was attenuated with lopinavir/ritonavir. Rosuvastatin AUC and Cmax were unexpectedly increased 2.1- and 4.7-fold in combination with lopinavir/ritonavir. Rosuvastatin and lopinavir/ritonavir should be used with caution until the safety, efficacy, and appropriate dosing of this combination have been demonstrated in larger populations.

Effects of Testosterone and Progressive Resistance Exercise in Healthy, Highly Functioning Older Men With Low-Normal Testosterone Levels

CONTEXT Aging in men is associated with reduced testosterone (T) levels and physiological changes leading to frailty, but the benefits of T supplementation are inconclusive. OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training (PRT) on functional performance, strength, and body composition. DESIGN, SETTING, AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men (66 ± 5 years) with low-normal baseline total T levels (200-350 ng/dL). INTERVENTION Subjects were randomized to placebo or transdermal T gel [2 doses targeting either a lower (400-550 ng/dL) or higher (600-1000 ng/dL) T range] and to either PRT or no exercise for 12 months. MAIN OUTCOME MEASURE The primary outcome was functional performance, whereas secondary outcomes were strength and body composition. RESULTS A total of 143 men completed the study. At 12 months, total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group. In the PRT group, function and strength were not different between T- and placebo-treated subjects, despite greater improvements in fat mass (P = .04) and fat-free mass (P = .01) with T. In the non-PRT group, T did not improve function but improved fat mass (P = .005), fat-free mass (P = .03), and upper body strength (P = .03) compared with placebo. There were fewer cardiovascular events in the T-treated groups compared with placebo. CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

Walking economy in people with Parkinson's disease.

Gait dysfunction is an early problem identified by patients with Parkinsons disease (PD). Alterations in gait may result in an increase in the energy cost of walking (i.e., walking economy). The purpose of this study was to determine whether walking economy is atypical in patients with PD when compared with healthy controls. A secondary purpose was to evaluate the associations of age, sex, and level of disease severity with walking economy in patients with PD. The rate of oxygen consumption (V̇O2) and other responses to treadmill walking were compared in 90 patients (64.4 ± 10.3 years) and 44 controls (64.6 ± 7.3 years) at several walking speeds. Pearson correlation coefficients (r) were calculated to determine relationships of age, sex, and disease state with walking economy in PD patients. Walking economy was significantly worse in PD patients than in controls at all speeds above 1.0 mph. Across all speeds, V̇O2 was 6 to 10% higher in PD patients. Heart rate, minute ventilation, respiratory exchange ratio, and rating of perceived exertion were correspondingly elevated. No significant relationship of age, sex, or UPDRS score with V̇O2 was found for patients with PD. The findings suggest that the physiologic stress of daily physical activities is increased in patients with early to mid‐stage PD, and this may contribute to the elevated level of fatigue that is characteristic of PD.

Mechanisms Associated with Dose-Dependent Inhibition of Rat Mammary Carcinogenesis by Dry Bean (Phaseolus vulgaris, L.)

The purpose of this study was to determine whether a dry bean (Phaseolus vulgaris, L.) containing diet exerts an inhibitory effect on mammary carcinogenesis in a well-characterized rodent model for breast cancer. Twenty-one-d-old female Sprague Dawley rats were given an intraperitoneal injection of 1-methyl-1-nitrosourea and 7 d after carcinogen injection were randomized to 1 of 5 groups fed a modification of the AIN-93G diet formulation containing 0, 7.5, 15, 30, or 60% (wt:wt) small red dry bean incorporated as cooked, freeze-dried, and milled powder. All experimental diets had the same macronutrient content based on proximate analysis. Compared with the control group, dry bean consumption resulted in dose-dependent reductions in mammary cancer incidence (P = 0.046), cancer multiplicity (P = 0.001), and tumor burden (P = 0.01). Dry bean consumption was associated with dose-dependent reductions in plasma concentrations of glucose, insulin, insulin-like growth factor-1, C-reactive protein, and interleukin-6 in food-deprived rats. Analysis of mammary adenocarcinomas indicated that a dominant mechanism accounting for reduced tumor burden was the induction of apoptosis. B cell lymphoma 2 and X-linked inhibitor of apoptosis protein levels decreased and BCL-2-associated X protein increased with increasing dry bean consumption, findings consistent with the induction of apoptosis via the mitochondrial pathway. These data demonstrate that a legume without noteworthy content of isoflavones inhibits the development of mammary carcinogenesis and are consistent with a recent report from the Nurses Health Study that bean or lentil intake is associated with a lower risk for breast cancer.

Muscle Strength and Functional Recovery During the First Year After THA

BackgroundPatients undergoing total hip arthroplasty (THA) often are satisfied with the decrease in pain and improvement in function they achieve after surgery. Even so, strength and functional performance deficits persist after recovery, but these remain poorly characterized; knowledge about any ongoing strength or functional deficits may allow therapists to design rehabilitation programs to optimize recovery after THA.Questions/purposesThe purposes of this study were to (1) evaluate postoperative muscle strength, function, and quality of life during the first year after THA; and (2) compare strength and function in patients 1 year after THA with a cohort of healthy peers.MethodsTwenty-six patients undergoing THA were assessed 1, 3, 6, and 12 months postoperatively, and 19 adults with no hip pathology were tested as a control group. Isometric muscle strength (hip flexors, extensors, abductors, knee extensors, and flexors), functional performance (stair climbing, five times sit-to-stand, timed-up-and-go, 6-minute walk, and single-limb stance tests), and self-reported function (Hip Disability and Osteoarthritis Score, SF-36, and UCLA activity score) were compared.ResultsOne month after THA, patients had 15% less hip flexor and extensor torque, 26% less abductor torque, 14% less knee extensor and flexor torque, and worse performance on the stair climbing, timed-up-and-go, single-limb stance, and 6-minute walk. Compared with healthy adults, patients 12 months after THA had 17% less knee extensor and 23% less knee flexor torque; however, the functional testing (including stair climbing, five times sit-to-stand, and the 6-minute walk) showed no significant differences with the patient numbers available between individuals undergoing THA and healthy control subjects. SF-36 Physical Component Scores, although significantly improved from preoperative levels, were significantly worse than healthy adults 1 year after THA (p < 0.01).ConclusionsPatients experience early postoperative strength losses and decreased functional capacity after THA, yet strength deficits may persist after recovery. This may suggest that rehabilitation may be most effective in the first month after surgery.Level of EvidenceLevel II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Relative Contributions of Adiposity and Muscularity to Physical Function in Community‐dwelling Older Adults

Objective: To determine the relative contributions of adiposity and muscularity to multi‐dimensional performance‐based and perceived physical function in older adults living independently.

Relationship Between Intensity of Quadriceps Muscle Neuromuscular Electrical Stimulation and Strength Recovery After Total Knee Arthroplasty

Background Neuromuscular electrical stimulation (NMES) can facilitate the recovery of quadriceps muscle strength after total knee arthroplasty (TKA), yet the optimal intensity (dosage) of NMES and its effect on strength after TKA have yet to be determined. Objective The primary objective of this study was to determine whether the intensity of NMES application was related to the recovery of quadriceps muscle strength early after TKA. A secondary objective was to quantify quadriceps muscle fatigue and activation immediately after NMES to guide decisions about the timing of NMES during rehabilitation sessions. Design This study was an observational experimental investigation. Methods Data were collected from 30 people who were 50 to 85 years of age and who received NMES after TKA. These people participated in a randomized controlled trial in which they received either standard rehabilitation or standard rehabilitation plus NMES to the quadriceps muscle to mitigate strength loss. For the NMES intervention group, NMES was applied 2 times per day at the maximal tolerable intensity for 15 contractions beginning 48 hours after surgery over the first 6 weeks after TKA. Neuromuscular electrical stimulation training intensity and quadriceps muscle strength and activation were assessed before surgery and 3.5 and 6.5 weeks after TKA. Results At 3.5 weeks, there was a significant association between NMES training intensity and a change in quadriceps muscle strength (R2=.68) and activation (R2=.22). At 6.5 weeks, NMES training intensity was related to a change in strength (R2=.25) but not to a change in activation (R2=.00). Furthermore, quadriceps muscle fatigue occurred during NMES sessions at 3.5 and 6.5 weeks, whereas quadriceps muscle activation did not change. Limitations Some participants reached the maximal stimulator output during at least 1 treatment session and might have tolerated more stimulation. Conclusions Higher NMES training intensities were associated with greater quadriceps muscle strength and activation after TKA.