The respective relevance of sensitization to alloantigens and xenoantigens in pig organ xenotransplantation.

BACKGROUND: Antibody-mediated rejection is a major cause of graft injury and contributes to failure of pig xenografts in nonhuman primates (NHPs). Most 'natural' or elicited antibodies found in humans and NHPs are directed against pig glycan antigens, but antibodies binding to swine leukocyte antigens (SLA) have also been detected. Of clinical importance is (i) whether the presence of high levels of antibodies directed towards human leukocyte antigens (HLA) (i.e., high panel-reactive antibodies) would be detrimental to the outcome of a pig organ xenograft; and (ii) whether, in the event of sensitization to pig antigens, a subsequent allotransplant would be at increased risk of graft failure due to elicited anti-pig antibodies that cross-react with human HLA or other antigens. SUMMARY: A literature review of pig-to-primate studies indicates that relatively few highly-HLA-sensitized humans have antibodies that cross-react with pigs, predicting that most would not be at increased risk of rejecting an organ xenograft. Furthermore, the existing evidence indicates that sensitization to pig antigens will probably not elicit increased alloantibody titers; if so, 'bridging' with a pig organ could be carried out without increased risk of subsequent antibody-mediated allograft failure. KEY MESSAGE: These issues have important implications for the design and conduct of clinical xenotransplantation trials.

Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor.

BACKGROUND: Here, we ask whether platelet GPIb and GPIIb/IIIa receptors modulate platelet sequestration and activation during GalTKO.hCD46 pig lung xenograft perfusion. METHODS: GalTKO.hCD46 transgenic pig lungs were perfused with heparinized fresh human blood. Results from perfusions in which αGPIb Fab (6B4, 10 mg/l blood, n = 6), αGPIIb/IIIa Fab (ReoPro, 3.5 mg/l blood, n = 6), or both drugs (n = 4) were administered to the perfusate were compared to two additional groups in which the donor pig received 1-desamino-8-d-arginine vasopressin (DDAVP), 3 µg/kg (to pre-deplete von Willebrand Factor (pVWF), the main GPIb ligand), with or without αGPIb (n = 6 each). RESULTS: Platelet sequestration was significantly delayed in αGPIb, αGPIb+DDAVP, and αGPIb+αGPIIb/IIIa groups. Median lung "survival" was significantly longer (>240 vs. 162 min reference, p = 0.016), and platelet activation (as CD62P and ßTG) were significantly inhibited, when pigs were pre-treated with DDAVP, with or without αGPIb Fab treatment. Pulmonary vascular resistance rise was not significantly attenuated in any group, and was associated with residual thromboxane and histamine elaboration. CONCLUSIONS: The GPIb-VWF and GPIIb/IIIa axes play important roles in platelet sequestration and coagulation cascade activation during GalTKO.hCD46 lung xenograft injury. GPIb blockade significantly reduces platelet activation and delays platelet sequestration in this xenolung rejection model, an effect amplified by adding αGPIIb/IIIa blockade or depletion of VWF from pig lung.

Lung Donation After Controlled Circulatory Determination of Death: A Review of Current Practices and Outcomes.

BACKGROUND: Since the first reported series in 1995, transplantation of lungs recovered through donation after circulatory determination of death (DCDD) has steadily increased. In some European and Australian centers, controlled DCDD accounts for 15% to 30% of all transplanted lungs. Several transplant centers have reported early and midterm outcomes similar to those associated with the use of donors after brain death. Despite these encouraging reports, less than 2% of all lung transplants in the United States are performed using donors after circulatory determination of death. METHODS: An electronic search from January 1990 to January 2014 was performed to identify series reporting lung transplant outcomes using controlled DCDD. Data from these publications were analyzed in terms of donor characteristics, donation after circulatory determination of death protocols, recipients' characteristics, and early and midterm outcomes. RESULTS: Two hundred twenty-two DCDDs were transplanted into 225 recipients. The rate of primary graft dysfunction grade 3 ranged from 3% to 36%. The need for extracorporeal membrane oxygenation support after transplantation ranged from 0% to 18%. The average intensive care unit stay ranged from 4 to 8.5 days and the average hospital stay ranged from 14 to 35 days. Thirty-day mortality ranged from 0% to 11% and 1-year survival from 88% to 100%. CONCLUSION: Under clinical protocols developed and strictly applied by several experienced lung transplant programs, lungs from controlled DCDD have produced outcomes very similar to those observed with brain death donors.

Expression of human CD46 modulates inflammation associated with GalTKO lung xenograft injury.

Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-α(1,3)-galactose epitope (GalTKO) and to express human CD46, a complement regulatory protein, has not previously been described. Physiologic, hematologic and biochemical parameters during perfusion with heparinized fresh human blood were measured for 33 GalTKO.hCD46, GalTKO (n = 16), and WT pig lungs (n = 16), and 12 pig lungs perfused with autologous pig blood. Median GalTKO.hCD46 lung survival was 171 min compared to 120 for GalTKO (p = 0.27) and 10 for WT lungs (p < 0.001). Complement activation, platelet activation and histamine elaboration were significantly reduced during the first 2 h of perfusion in GalTKO.hCD46 lungs compared to GalTKO (ΔC3a at 120' 812 ± 230 vs. 1412 ± 1047, p = 0.02; ΔCD62P at 120' 9.8 ± 7.2 vs. 25.4 ± 18.2, p < 0.01; Δhistamine at 60' 97 ± 62 vs. 189 ± 194, p = 0.03). We conclude that, in addition to significant down-modulation of complement activation, hCD46 expression in GalTKO lungs diminished platelet and coagulation cascade activation, neutrophil sequestration and histamine release. Because GalTKO.hCD46 lung failure kinetics correlated directly with platelet and neutrophil sequestration, coagulation cascade activation and a rise in histamine levels within the first hour of perfusion, further progress will likely depend upon improved control of these pathways, by rationally targeted additional modifications to pigs and pharmacologic interventions.

Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival.

Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ≈ 50 000 islet equivalents/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation.

B-cell depletion extends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months.

Xenotransplantation of genetically modified pig organs offers great potential to address the shortage of human organs for allotransplantation. Rejection in Gal knockout (GTKO) pigs due to elicited non-Gal antibody response required further genetic modifications of donor pigs and better control of the B-cell response to xenoantigens. We report significant prolongation of heterotopic alpha Galactosyl transferase "knock-out" and human CD46 transgenic (GTKO.hCD46Tg) pig cardiac xenografts survival in specific pathogen free baboons. Peritransplant B-cell depletion using 4 weekly doses of anti-CD20 antibody in the context of an established ATG, anti-CD154 and MMF-based immunosuppressive regimen prolonged GTKO.hCD46Tg graft survival for up to 236 days (n = 9, median survival 71 days and mean survival 94 days). B-cell depletion persisted for over 2 months, and elicited anti-non-Gal antibody production remained suppressed for the duration of graft follow-up. This result identifies a critical role for B cells in the mechanisms of elicited anti-non-Gal antibody and delayed xenograft rejection. Model-related morbidity due to variety of causes was seen in these experiments, suggesting that further therapeutic interventions, including candidate genetic modifications of donor pigs, may be necessary to reduce late morbidity in this model to a clinically manageable level.

Fat-free mass index: changes and race/ethnic differences in adulthood.

OBJECTIVE: Nutritional status is assessed by measuring BMI or percent body fat (%fat). BMI can misclassify persons who carry more weight as fat-free mass and %fat can be misleading in cases of malnutrition or in disease states characterized by wasting of lean tissue. The fat-free mass index (FFMI) is proposed to assess body composition in individuals who have a similar body composition but differ in height allowing identification of those suffering from malnutrition, wasting or those that possess a relatively high muscle mass. The purpose was to determine whether the FFMI differs in a group of racially/ethnically diverse adults. DESIGN: Cross-sectional. SUBJECTS: Subjects were a multi-ethnic sample (Caucasian, CA; African American, AA; Hispanic, HIS and Asian, AS) of 1339 healthy males (n = 480) and females (n = 859) ranging in age from 18-110 years. Total body fat, total fat-free mass and bone mineral density were estimated using dual energy X-ray absorptiometry. RESULTS: FFMI differed among the four ethnic groups (P ≤ 0.05) for both genders. A curvilinear relationship was found between age and FFMI for both genders although the coefficients in the quadratic model differed between genders (P ≤ 0.001) indicating the rate of change in FFMI differed between genders. The estimated turning point where FFMI started to decline was in the mid 20s for male and mid 40s for female participants. An age × gender interaction was found such that the rate of decline was greater in male than female participants (P ≤ 0.001). For both genders, FFMI was greatest in AA and the least in AS (P ≤ 0.001). There was no significant interaction between race and age or age(2) (P = 0.06). However, male participants consistently had a greater FFMI than female participants (P ≤ 0.001). CONCLUSIONS: These findings have clinical implications for identifying individuals who may not be recognized as being malnourished based on their BMI or %fat but whose fat-free mass corrected for height is relatively low.

Elderly Mexicans have less muscle and greater total and truncal fat compared to African-Americans and Caucasians with the same BMI.

BACKGROUND: How body composition, specifically skeletal muscle mass, compares in Mexican elderly to other ethnic groups has not previously been reported. We tested the hypothesis that older adults from Northwest Mexico (Mex) would have similar total appendicular skeletal muscle (TASM) compared with New York dwelling Caucasians (Cauc) and African-Americans (AA). METHODS: Two hundred and eighty nine Mex (135 males and 154 females), 166 AA (36 males and 130 females) and 229 Cauc (64 males and 165 females), aged 60-98 years were assessed. Total and regional fat and lean tissues were measured by whole-body dual energy X-ray absorptiometry where TASM is the sum of arm and leg bone-free and fat-free lean tissue. Differences in TASM were tested by ANCOVA, with age, height, and body mass index (BMI) as covariates. RESULTS: TASM adjusted for ethnicity, age, height and BMI, were 22.6 +/- 0.2 kg and 17.8 +/- 0.1 kg for males and females, respectively (p < 0.001). Among males with similar age, height, and BMI, Mex had less TASM compared with AA and Cauc (p < 0.001). Total body fat and truncal fat were higher (p < 0.001) and FFM lower (p < 0.001) in Mex compared to both AA and Cauc males after adjusting for age and BMI. Among females, Mex had higher total and truncal fat (p < 0.001) after adjusting for age and BMI, and significantly lower TASM (p < 0.001) after adjusting for age, height, and BMI compared to AA and Cauc females. CONCLUSIONS: Elderly Mex have a different body composition compared with AA and Cauc of a similar BMI and age. Mex have significantly less TASM with greater total and truncal fat. In the long-term, Mex elderly may be at greater risk for sarcopenic obesity compared to other ethnic groups.

Body composition analysis: Cellular level modeling of body component ratios.

During the past two decades, a major outgrowth of efforts by our research group at St. Luke's-Roosevelt Hospital is the development of body composition models that include cellular level models, models based on body component ratios, total body potassium models, multi-component models, and resting energy expenditure-body composition models. This review summarizes these models with emphasis on component ratios that we believe are fundamental to understanding human body composition during growth and development and in response to disease and treatments. In-vivo measurements reveal that in healthy adults some component ratios show minimal variability and are relatively 'stable', for example total body water/fat-free mass and fat-free mass density. These ratios can be effectively applied for developing body composition methods. In contrast, other ratios, such as total body potassium/fat-free mass, are highly variable in vivo and therefore are less useful for developing body composition models. In order to understand the mechanisms governing the variability of these component ratios, we have developed eight cellular level ratio models and from them we derived simplified models that share as a major determining factor the ratio of extracellular to intracellular water ratio (E/I). The E/I value varies widely among adults. Model analysis reveals that the magnitude and variability of each body component ratio can be predicted by correlating the cellular level model with the E/I value. Our approach thus provides new insights into and improved understanding of body composition ratios in adults.

Truncal fat in relation to total body fat: influences of age, sex, ethnicity and fatness.

OBJECTIVE: To investigate the influence of age, sex, ethnicity and total fatness on central obesity in four ethnic populations. DESIGN: Cross-sectional analysis of study subjects enrolled from 1993 to 2005. SUBJECTS: A multi-ethnic (Caucasian (CA), African-American (AA), Hispanic-American (HA) and Asian (As)) convenience sample of 604 men and 1192 women (aged 18-96 years, body mass index 15.93-45.80 kg/m(2)). MEASUREMENTS: Total body fat (TBF) and truncal fat were measured by dual-energy X-ray absorptiometry. General linear regression models were used to test for independent associations with log(10)-transformed truncal fat. RESULTS: For all ethnicities, men had a lower percent body fat and more truncal fat than women. Log(10-)transformed truncal fat increased with TBF approximately as a square root function. At older ages, there was a greater amount of truncal fat in CA, HA and As men (approximately 0.20-0.25 kg/decade) with the effect more pronounced in AA men ( approximately 0.33 kg/decade). For women, the increment of truncal fat per decade was reduced in CA and AA women (approximately 0.07 kg) compared with As and HA women (approximately 0.33 kg). Adjusted for mean values of covariates in our sample, AA had less truncal fat than As. CONCLUSION: The accumulation of truncal fat is strongly related to age, ethnicity and total fatness in both men and women.

Effect of age on outcomes after left ventricular assist device placement.

The influence of age on outcomes after left ventricular assist device (LVAD) implantation is not well studied. To address this question, we assessed 222 patients who underwent LVAD placement and were divided into quartiles based on age (years): group 1, or=60. Eighty-four patients died on LVAD support. Six- and 12-month survivals for the four groups of LVAD patients were 67.7, 73.7, 49.8, and 38.2, and 49.4, 57.3, 42.7, and 26.2, respectively (all P<.01). Older patients showed a higher risk of infections, embolic strokes, and respiratory complications. They were the least likely to undergo reoperations postimplantation (56%, 53%, 50%, 46%, P=.06). After adjusting for baseline differences between the groups, there was a trend toward increasing mortality with age, which did not reach significance (odds ratio 1.93; 95% confidence interval 0.95 to 3.92 for the oldest quartile as compared with the youngest). In conclusion, these results suggest in the absence of other high risk factors, age alone should not be used as an independent contraindication for LVAD implantation.

A single-season prospective study of respiratory viral infections in lung transplant recipients.

The frequency and complications of respiratory viral infections (RVI) were studied in 50 ambulatory lung transplant patients during a single winter season, using viral antigens, viral cultures and PCR of nasal washes or bronchoalveolar lavages. Patients' survival, episodes of acute rejection and occurrence of bronchiolitis obliterans (BO) or BO syndrome (BOS) were monitored for 1 yr after the study. Overall, 32 (64%) patients had 49 symptomatic episodes. Documented infections included eight due to respiratory syncytial virus (RSV), one due to parainfluenza virus (PIV) and 10 due to influenza (FLU). Four of the FLU infections were serological rises without symptoms. Overall, 17 (34%) patients had documented viral infection; four patients had lower respiratory involvement and two (one RSV, one PIV) were hospitalised for aerosolised ribavirin treatment. After 1 yr there were three (6%) deaths unrelated to RVI. BO or BOS had occurred in one (6%) out of 17 patients with and three (12%) out of 33 without RVI. Respiratory viruses infected one-third of ambulatory lung transplant recipients in a single season. In conclusion, respiratory viral infection was not associated with subsequent graft dysfunction. Larger prospective studies are required to better define the acute and long-term morbidity of these infections.

Hyperacute rejection is attenuated in GalT knockout swine lungs perfused ex vivo with human blood.

BACKGROUND: Hyperacute rejection (HAR) is one of the principal obstacles to successful xenotransplantation. Homozygous alpha-1,3-galactosyltransferase knockout (GalT-KO) miniature swine now offer the prospect of overcoming this barrier to xenotransplantation. In this study, the short-term function of GalT-KO swine lungs was evaluated in a well-established ex vivo model of swine-to-human lung xenotransplantation. METHODS: Lungs from homozygous GalT-KO swine (n = 3) and control lungs from pigs of the background strain used to create the GalT-KO pig line (n = 2) were perfused ex vivo with freshly collected heparinized human blood. Graft function was assessed by various physiologic measurements, serial histologic and immunohistochemical evaluation, and assays of complement and platelet activation. RESULTS: Xenoperfused control swine lungs exhibited HAR with graft survival times <5 minutes. In contrast, GalT-KO swine lungs retained their function for approximately 2 hours, on average. GalT-KO swine lungs showed decreased complement and platelet activation compared with controls. Nonetheless, activation of complement and coagulation cascades was not completely eliminated in the GalT-KO swine lungs. CONCLUSIONS: The survival of xenoperfused GalT-KO swine lungs was significantly prolonged, as compared with control lungs expressing Gal. This appears to have been due largely to substantially reduced complement activation. Nonetheless, the xenoperfused GalT-KO lungs still showed some evidence of complement fixation and intravascular coagulopathy by the time of graft demise.

Relation of BMI to fat and fat-free mass among children and adolescents.

OBJECTIVE: Although the body mass index (BMI, kg/m2) is widely used as a surrogate measure of adiposity, it is a measure of excess weight, rather than excess body fat, relative to height. We examined the relation of BMI to levels of fat mass and fat-free mass among healthy 5- to 18-y-olds. METHODS AND PROCEDURES: Dual-energy X-ray absorptiometry was used to measure fat and fat-free mass among 1196 subjects. These measures were standardized for height by calculating the fat mass index (FMI, fat mass/ht2) and the fat-free mass index (FFMI, fat-free mass/ht2). RESULTS: The variability in FFMI was about 50% of that in FMI, and the accuracy of BMI as a measure of adiposity varied greatly according to the degree of fatness. Among children with a BMI-for-age > or =85th P, BMI levels were strongly associated with FMI (r=0.85-0.96 across sex-age categories). In contrast, among children with a BMI-for-age <50th P, levels of BMI were more strongly associated with FFMI (r=0.56-0.83) than with FMI (r=0.22-0.65). The relation of BMI to fat mass was markedly nonlinear, and substantial differences in fat mass were seen only at BMI levels > or =85th P. DISCUSSION: BMI levels among children should be interpreted with caution. Although a high BMI-for-age is a good indicator of excess fat mass, BMI differences among thinner children can be largely due to fat-free mass.

Pencil-beam versus fan-beam dual-energy X-ray absorptiometry comparisons across four systems: appendicular lean soft tissue.

Dual-energy X-ray absorptiometry (DXA) provides an important opportunity for estimating total body skeletal muscle (SM) mass from DXA-measured appendicular lean soft tissue (ALST). A DXA SM prediction model was developed with magnetic resonance imaging as the reference and ALST (i. e., sum of arm plus leg lean soft tissue) as a main predictor variable. In the present study we examined whether ALST estimates are comparable across systems (i. e., penciland fan-beam) and manufacturers. Pencil-beam systems (Lunar DPX and DPX-L) are usually considered more accurate but slower than fan-beam systems (Lunar Prodigy and Hologic Delphi A). In this study we compared ALST estimates in 35 healthy adults across these four systems. The methods gave similar group mean (+/-SD) values and were highly intercorrelated. There was no significant bias detected across the four systems. ALST estimates from the evaluated DXA systems are comparable and thus appear interchangeable as methods for quantifying total body SM in vivo.

A brief history of body composition-from F. D. Moore to the new Reference Man.

The history of applying body composition measurements to physiology is short, well less than a century. Progress has been phenomenal, on three different fronts: tracer dilution methods, neutron activation methods, and imaging methods. The latter have seen the most recent and exciting advances, and we have probably just "scratched the surface" for the futures of imaging, with spectroscopy showing great promise. However the physiological principles established in the 1950-1980 era are the reason we are here; measurements that lead to diagnosis, treatment, and understanding of disease mechanisms. The future is very bright.

The relationship between body mass index and body cell mass in African-American, Asian, and Caucasian adults.

The objective of this study was to investigate the relationship between body mass index (BMI, kg/m(2)) and body cell mass (BCM) estimated from total body potassium (TBK) measured by whole body (40)K counting in healthy 284 African-Americans (AA), 269 Asians (A) and 536 Caucasians (C) aged 18-107 years and to study the effects of age, sex, and race on the relationship. Body fat and fat-free mass (FFM) were measured by dual-energy X-ray absorptiometry (DXA). There was a significant positive correlation between BCM and BMI. For a given BMI, A had lower BCM but decreased less per year of age than AA and C, and males had higher BCM than females in each ethnic group. The fraction, BCM/FFM decreased with BMI in all subgroups by race, sex, and age, and males decreased more per age and AA decrease more than A and C. Not only the BCM-BMI relationship but also BCM/FFM vs. BMI is important to health.

Is there an association between skeletal muscle mass and bone mineral density among African-American, Asian-American, and European-American women?

Skeletal muscle strength is a factor in the growth and maintenance of bone density and both skeletal muscle mass and bone mineral density are related to bone fracture risk. We studied the relationship between total body bone mineral density (TBBMD) and total appendicular skeletal muscle mass (TASM) estimated by dual-energy X-ray absorptiometry (DEXA) in African-American (AA), Asian-American (AsA), and European-American (EA) premenopausal (PRM) and postmenopausal (POM) women. The age- and weight-adjusted TBBMD-TASM association was positive in all PRM race groups and in POM EA, but was negative in POM AA and POM AsA. Body weight and age were positively and negatively associated with TBBMD, respectively, and the relationship was stronger in POM. In all race groups the variability in TBBMD was significantly greater in POM women.

Hyperacute lung rejection in the pig-to-human model. 2. Synergy between soluble and membrane complement inhibition.

BACKGROUND: The role of complement in hyperacute lung xenograft rejection has not been elucidated. The present study evaluates the effect of complement (C) C3/C5 convertase inhibition on hyperacute rejection of pig lung by human blood. METHODS: In an established ex-vivo model, lungs from pigs heterozygous for human decay accelerating factor (hDAF), non-transgenic littermate control pigs, or farm-bred pigs were perfused with fresh human blood that was either unmodified or treated with soluble complement receptor type 1 (sCR1: TP10, 100 microg/ml). RESULTS: Non-transgenic lungs from littermate controls had a median survival time of 35 min (range 5 to 210; P = 0.25 vs. farm-bred piglets: median 5 min, range 5 to 10). Lungs expressing hDAF survived for a median of 90 min (range 10 to 161; P = 0.5 and 0.01 vs. littermate and farm-bred controls, respectively), with sCR1, whereas hDAF (-) lungs failed by 35 min (range 6 to 307), hDAF (+) lungs survived for 330 min (range 39 to 577) [P = 0.002 vs. farm-bred; P = 0.08 vs. hDAF (-); P = 0.17 vs. sCR1/hDAF (-)]. The rise in pulmonary vascular resistance (PVR) at 5 min was blunted only by hDAF (+) with sCR1 (0.26 +/- 0.2 vs. 0.5 to 0.7 mmHg/ml/min for other groups). Plasma C3a and sC5b-9 and tissue deposition of C5b-9 were dramatically diminished using sCR1, and further decreased in association with hDAF. Histamine and thromboxane were produced rapidly in all groups. CONCLUSION: Complement plays an important role in lung HAR. However, even potent inhibition of C3/C5 convertase, both membrane bound in lung and by a soluble-phase inhibitor in the blood, does not prevent activation of inflammatory responses known to be particularly injurious to the lung. Our findings implicate a role for innate immune pathways resistant to efficient complement regulation. The role of anti-species antibody, coagulation pathway dysregulation, and additional environmental or genetic influences remain to be defined.

Effects of whey protein and resistance exercise on body cell mass, muscle strength, and quality of life in women with HIV.

OBJECTIVE: To determine the effects of whey protein, resistance exercise, and combined protein and exercise treatment on body cell mass (BCM), muscle strength, and quality of life (QOL) in HIV-infected women with reduced BCM. DESIGN AND SETTING: Prospective, randomized, controlled trial at a university hospital in New York City. METHODS: A volunteer sample of 30 HIV-infected women were randomized to whey protein (PRO), progressive resistance exercise (PRE), or combined treatment (PRO-PRE) for 14 weeks after a 6-week control period. The main outcome measures were body weight, BCM, skeletal muscle, fat mass, muscle strength, and QOL. RESULTS: There were no significant changes in BCM, strength, or QOL during the control period. PRO patients gained 3.6 kg (P = 0.001), and 2.5 kg fat (P = 0.002) with no change in BCM (0.5 kg; P = 0.07) or skeletal muscle (0.6 kg; P = 0.12). The PRE group increased BCM (0.74 kg;P = 0.03) and skeletal muscle (1.2 kg; P < 0.001) and decreased fat (1.7 kg; P = 0.02). PRO-PRE increased BCM (0.61 kg; P = 0.01) without change in skeletal muscle (0.6 kg; P = 0.30). Strength increased for both exercise groups (range, 40.6-95.3%; P < 0.001). The QOL physical activity score improved for PRE (P = 0.02) and worsened for PRO (P = 0.01). CONCLUSIONS: Resistance exercise significantly increased BCM, muscle mass, muscle strength, and QOL in HIV-infected women with reduced BCM. Whey protein had little effect on BCM accrual. Combined protein and exercise did not increase BCM in excess of gains achieved by exercise alone.