A cell-based drug delivery platform for treating central nervous system inflammation.

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.

Cross-Validation of Resting Metabolic Rate Prediction Equations.

BACKGROUND: Resting metabolic rate (RMR) measurement is time consuming and requires specialized equipment. Prediction equations provide an easy method to estimate RMR; however, their accuracy likely varies across individuals. Understanding the factors that influence the accuracy of RMR predictions will help to revise existing, or develop new and improved, equations. OBJECTIVE: Our aim was to test the validity of RMR predicted in healthy adults by the Harris-Benedict, World Health Organization, Mifflin-St Jeor, Nelson, Wang equations, and three meta-equations of Sabounchi. DESIGN: Predicted RMR was tested for agreement with indirect calorimetry. PARTICIPANTS/SETTING: Men and women (n=30) age 18 to 65 years from Grand Forks, ND, were recruited and included for analysis during spring/summer 2014. Participants were nonobese or obese (body mass index range=19 to 39) and primarly white. MAIN OUTCOME MEASURE: Agreement between measured (indirect calorimetry) and predicted RMR was measured. STATISTICAL ANALYSIS: The methods of Bland and Altman were employed to determine mean bias (predicted minus measured RMR, kcal/day) and limits of agreement between predicted and measured RMR. Repeated-measures analysis of variance was used to test for bias in RMR predicted from each equation vs the measured RMR. RESULTS: Bias (mean±2 standard deviations) was lowest for the Harris-Benedict (-14±378 kcal/24 h) and World Health Organization (-25±394 kcal/24 h) equations. These equations also predicted RMR that were not different from measured. Mean RMR predictions from all other equations significantly differed from indirect calorimetry. The 2 standard deviation limits of agreement were moderate or large for all equations tested, ranging from 314 to 445 kcal/24 h. Prediction bias was inversely associated with the magnitude of RMR and with fat-free mass. CONCLUSIONS: At the group level, the traditional Harris-Benedict and World Health Organization equations were the most accurate. However, these equations did not perform well at the individual level. As fat-free mass increased, the prediction equations further underestimated RMR.

Reduction of inflammation and preservation of neurological function by anti-CD52 therapy in murine experimental autoimmune encephalomyelitis.

Alemtuzumab, a monoclonal antibody directed against human CD52, is used in the treatment of MS. To characterize the impact of anti-CD52 administration, a monoclonal antibody to mouse CD52 (anti-muCD52) was generated and evaluated in EAE mouse models of MS. A single course of anti-muCD52 provided a therapeutic benefit accompanied by a reduction in the frequency of autoreactive T lymphocytes and production of pro-inflammatory cytokines. Examination of the CNS revealed a decrease in infiltrating lymphocytes, demyelination and axonal loss. Electrophysiological assessment showed preservation of axonal conductance in the spinal cord. These findings suggest that anti-CD52 therapy may help preserve CNS integrity.

Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro.

Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon-ß in relapsing-remitting multiple sclerosis patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Treg cells) has been observed in multiple sclerosis patients after alemtuzumab. Since Treg cells play an important role in the control of autoimmune responses, the effect of alemtuzumab on Treg cells was further studied in vitro. Alemtuzumab effectively mediated complement-dependent cytolysis of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab-exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg cell frequency, the CD25(hi) T-cell population was necessary for the suppressive activity of alemtuzumab-exposed T cells. The mechanism of this suppression was found to be dependent on both cell-cell contact and interleukin-2 consumption. These findings suggest that an alemtuzumab-mediated increase in the proportion of Treg cells may play a role in promoting the long-term efficacy of alemtuzumab in patients with multiple sclerosis.

Immune status following alemtuzumab treatment in human CD52 transgenic mice.

Alemtuzumab is a monoclonal antibody against the CD52 antigen present at high levels on the surface of lymphocytes. While treatment of multiple sclerosis patients with alemtuzumab results in marked depletion of lymphocytes from the circulation, it has not been associated with a high incidence of serious infections. In a human CD52 transgenic mouse, alemtuzumab treatment showed minimal impact on the number and function of innate immune cells. A transient decrease in primary adaptive immune responses was observed post-alemtuzumab but there was little effect on memory responses. These results potentially help explain the level of immunocompetence observed in alemtuzumab-treated MS patients.

Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists.

The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.

Felder-Soloman's Index of Learning Styles: internal consistency, temporal stability, and factor structure.

BACKGROUND: Strategies to facilitate learning include using knowledge of students' learning style preferences to inform students and their teachers. PURPOSE: Aims of this study were to evaluate the factor structure, internal consistency, and temporal stability of medical student responses to the Index of Learning Styles (ILS) and determine its appropriateness as an instrument for medical education. METHODS: The ILS assesses preferences on four dimensions: sensing/intuitive information perceiving, visual/verbal information receiving, active/reflective information processing, and sequential/global information understanding. Students entering the 2002-2007 classes completed the ILS; some completed the ILS again after 2 and 4 years. RESULTS: Analyses of responses supported the ILS's intended structure and moderate reliability. Students had moderate preferences for sensing and visual learning. CONCLUSIONS: This study provides evidence supporting the appropriateness of the ILS for assessing learning style preferences in medical students.

Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models.

Alemtuzumab is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to correlate with the anti-tumor activity of alemtuzumab. Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody, thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.

Body density estimates from upper-body skinfold thicknesses compared to air-displacement plethysmography.

BACKGROUND & AIMS: Determine the accuracy of body density (Db) estimated with upper-body skinfold thickness (SFT) measurements compared to air-displacement plethysmography (ADP) and ascertain whether body mass index (BMI) impacts the accuracy of SFT to assess Db. METHODS: We estimated Db with SFT and ADP in 131 healthy men and women with normal (N; 18.5-24.9kg/m(2)), overweight (OW; 25-29.9kg/m(2)), and obese (OB; 30-39.9kg/m(2)) BMI. RESULTS: Compared with ADP, SFT overestimated (p<0.05) Db in OW and OB females and in OB males (-0.0047, -0.0164 and -0.0119g/cc, respectively), and underestimated (p<0.05) Db in N females and males (0.0050 and 0.0068g/cc, respectively) but did not differently estimate Db in OW males. The gender by BMI group interaction was not significant. SFT underestimated (p<0.05; 0.0058g/cc) Db in the N and overestimated (p<0.05; 0.0113g/cc) Db in the OB BMI groups. The error in predicting Db did not change significantly over the range of Db within the N (r=0.239, p=0.06) and OB (r=0.160, p=0.934) BMI groups. Limits of agreement were -0.0165 to 0.0284g/cc and -0.0365 to 0.0085g/cc for the N and OB BMI groups, respectively. The error of estimating Db with SFT was correlated with mean Db in the aggregate sample (r=0.495, p<0.0001) and the OW group (r=0.394, p<0.009). The regression-based limits of agreement were +/-0.0226g/cc in the total group and +/-0.0168g/cc in the OW group. CONCLUSIONS: Although SFT offer practical advantages, the validity of SFT to estimate Db among individuals with N and OB BMI is adversely affected.

Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model.

Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of normal and malignant lymphocytes. It is approved for the treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III clinical trials for the treatment of multiple sclerosis. The exact mechanism by which alemtuzumab mediates its biological effects in vivo is not clearly defined and mechanism of action studies have been hampered by the lack of cross-reactivity between human and mouse CD52. To address this issue, a transgenic mouse expressing human CD52 (hCD52) was created. Transgenic mice did not display any phenotypic abnormalities and were able to mount normal immune responses. The tissue distribution of hCD52 and the level of expression by various immune cell populations were comparable to those seen in humans. Treatment with alemtuzumab replicated the transient increase in serum cytokines and depletion of peripheral blood lymphocytes observed in humans. Lymphocyte depletion was not as profound in lymphoid organs, providing a possible explanation for the relatively low incidence of infection in alemtuzumab-treated patients. Interestingly, both lymphocyte depletion and cytokine induction by alemtuzumab were largely independent of complement and appeared to be mediated by neutrophils and natural killer cells because removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively, strongly inhibited the activity of alemtuzumab whereas removal of complement by treatment with cobra venom factor had no impact. The hCD52 transgenic mouse appears to be a useful model and has provided evidence for the previously uncharacterized involvement of neutrophils in the activity of alemtuzumab.

Validity of segmental multiple-frequency bioelectrical impedance analysis to estimate body composition of adults across a range of body mass indexes.

OBJECTIVE: We compared body composition estimates using an eight-electrode, segmental, multiple-frequency bioelectrical impedance analysis (segmental MF-BIA) and dual x-ray absorptiometry (DXA) in a group of healthy adults with a range of body mass indexes (BMIs). METHODS: Percentage of body fat (%BF), fat-free mass, and fat mass assessed by DXA and segmental MF-BIA in 132 healthy adults were classified by normal (N; 18.5-24.9 kg/m(2)), overweight (OW; 25-29.9 kg/m(2)), and obese (OB; 30-39.9 kg/m(2)) BMI. RESULTS: Compared with DXA, segmental MF-BIA overestimated %BF in the OB BMI group (3.4%; P < 0.0001). MF-BIA overestimated %BF among men (0.75%; P < 0.006) and women (0.87%; P < 0.006) and underestimated it in the N BMI group (-1.56%; P < 0.0001); %BF was not different between methods in the OW BMI group. Error in %BF determined by segmental MF-BIA and DXA increased as %BF increased (r = 0.42, P < 0.0001). Waist circumference was the only significant predictor of systematic error in %BF between MF-BIA and DXA (r = 0.60, P < 0.0001). CONCLUSION: Eight-electrode, segmental MF-BIA is a valid method to estimate %BF in adults with BMI classified as N and OW, but not as OB. Estimation of trunk resistance with current segmental MF-BIA devices may explain the underestimation of %BF in the adults with OB BMI. Further examination of the effect of waist circumference and body fat distribution on the accuracy of BIA measurements is warranted.

Cytotoxic T lymphocyte responses to transgene product, not adeno-associated viral capsid protein, limit transgene expression in mice.

The use of adeno-associated viral (AAV) vectors for gene replacement therapy is currently being explored in several clinical indications. However, reports have suggested that input capsid proteins from AAV-2 vector particles may result in the stimulation of cytotoxic T lymphocyte (CTL) responses that can result in a loss of transduced cells. To explore the impact of anti-AAV CTLs on AAV-mediated transgene expression, both immunocompetent C57BL=6 mice and B cell-deficient muMT mice were immunized against the AAV2 capsid protein (Cap) and were injected intravenously with an AAV-2 vector encoding alpha-galactosidase (alpha-Gal). C57BL=6 mice, which developed both CTL and neutralizing antibody responses against Cap, failed to show any detectable alpha-Gal expression. In contrast, serum alpha-Gal levels comparable to those of naive mice were observed in muMT mice despite the presence of robust CTL activity against Cap, indicating that preexisting Cap-specific CTLs did not have any effect on the magnitude and duration of transgene expression. The same strategy was used to assess the impact of CTLs against the alpha-Gal transgene product on AAV-mediated gene delivery and persistence of transgene expression. Preimmunization of muMT mice with an Ad=alpha-Gal vector induced a robust CTL response to alpha-Gal. When these mice were injected with AAV2=alpha-Gal vector, initial levels of alpha-Gal expression were reduced by more than 1 log and became undetectable by 2 weeks postinjection. Overall, our results indicate that CTLs against the transgene product as opposed to AAV capsid protein are more likely to interfere with AAV transgene expression.

Induction of antitumor immunity by semi-allogeneic and fully allogeneic electrofusion products of tumor cells and dendritic cells.

Immunization with the electrofusion product of tumor cells and dendritic cells (DCs) is a promising approach to cancer immunotherapy. Production of electrofusion vaccines currently requires the acquisition of tumor material and must be tailored to each individual. Alternative vaccine configurations were explored in this study. Results indicated that fusion vaccines with fully syngeneic, semi-allogeneic or fully allogeneic components, were all effective in inducing specific, long-lasting antitumor immunity. This previously undescribed activity of a fully allogeneic fusion product introduces the possibility of using defined allogeneic tumor and DC lines to simplify vaccine manufacturing.

Interaction of clothing and body mass index affects validity of air-displacement plethysmography in adults.

OBJECTIVE: We determined the effect of clothing type on the validity of air-displacement plethysmography (ADP) to estimate percentage of body fat (%BF) and ascertain if these effects differ by body mass index (BMI). METHODS: The %BF by dual x-ray absorptiometry (DXA) and %BF, density, and body volume by ADP were assessed in 132 healthy adults classified by normal (N; 18.5-24.9 kg/m2), overweight (OW; 25-29.9 kg/m2), and obese (OB; 30-39.9 kg/m2) BMIs. RESULTS: Compared with DXA, ADP underestimated (P < 0.0001) %BF from scrubs (SC) and t-shirt/shorts (TS) in N (11.4%; 8.6%) and OW (6.8%; 4.9%) BMI groups, respectively. ADP compared with DXA overestimated (P < 0.0006) %BF in the OW group (1.2%), but underestimated (P < 0.0001) it in the N group (2.4%). ADP also overestimated (P < 0.006) %BF in the OB group wearing spandex (SP; 4.8%), but not in those wearing SC (0.7%; P = 0.10) and TS (0.5%; P = 0.22) versus DXA. CONCLUSION: All three clothing types showed significant error in estimating %BF with ADP compared with DXA in N and OW BMI. Use of spandex provided the least error and is the preferred attire to obtain valid body composition results when testing N and OW subjects. However, SP provided the greatest error in the OB group. Error in ADP %BF in OB was minimal in SC and TS and similar to the within-subject variability in %BF estimates with ADP. Thus, TS and SC are acceptable alternatives to SP in adults with excess body weight.

Assessment of change in hydration in women during pregnancy and postpartum with bioelectrical impedance vectors.

OBJECTIVE: This study tested the hypothesis that bioelectrical impedance vectors, group and individual, are valid indicators of total body water (TBW) and hydration status in women experiencing fluid gain and loss during and after pregnancy. METHODS: We measured TBW, assessed with D(2)O dilution, and resistance (R) and reactance (Xc), determined with 800 microA at 50 kHz and standardized for height (H) and plotted on a bivariate (R-Xc) graph, in 15 women, 21-37 y of age, longitudinally before and during pregnancy and postpartum (PP). RESULTS: Body weight (61.9 +/- 2.3 to 75.5 +/- 2.3 kg) and TBW (31.4 +/- 1.1 to 38.2 +/- 1.1 L) increased (P < 0.05) from before pregnancy to the third trimester of pregnancy and decreased PP (67.0 +/- 2.3 kg and 32.7 +/- 1.1 L, P < 0.05). R/H and Xc/H decreased during pregnancy (P < 0.05, 361 +/- 10 to 318 +/- 10 and 44 +/- 1 to 36 +/- 1 omega/m, respectively) and increased PP (P < 0.05, 355 +/- 10 and 41 +/- 1 Omega/m). Vector length decreased (P < 0.05, 363 +/- 10 to 320 +/- 10 Omega) during pregnancy and increased PP (P < 0.05, 357 +/- 10 Omega). Changes in vector length and TBW during pregnancy and PP were correlated (r = -0.599, P < 0.001). Women with vectors exceeding a 75% tolerance interval had greater TBW gain (10-12 versus 5-6 L) during pregnancy compared with other women with vectors within this tolerance level. CONCLUSION: These findings indicate that impedance vectors provide quantitative evidence of hydration status during pregnancy and that the impedance vector method is useful in monitoring hydration status in pregnancy.

Chromium picolinate supplementation in women: effects on body weight, composition, and iron status.

OBJECTIVE: This study tested the hypothesis that supplementation of chromium picolinate (CrPic), 200 microg Cr/d, compared with an equivalent amount of picolinic acid (1720 microg) in CrPic and placebo, decreases body weight, alters body composition, and reduces iron status of women fed diets of constant energy and nutrients. METHODS: We fed 83 women nutritionally balanced diets, used anthropometry and dual x-ray absorptiometry to assess body composition, and measured serum and urinary Cr and biochemical indicators of iron status before and serially every 4 wk for 12 wk in a double-blind, randomized trial. RESULTS: CrPic supplementation increased (P < 0.0001) serum Cr concentration and urinary Cr excretion compared with picolinic acid and placebo. CrPic did not affect body weight or fat, although all groups lost (P < 0.05) weight and fat; it did not affect fat-free, mineral-free mass or measurements of iron status. CONCLUSION: Under conditions of controlled energy intake, CrPic supplementation of women did not independently influence body weight or composition or iron status. Thus, claims that supplementation of 200 microg of Cr as CrPic promotes weight loss and body composition changes are not supported.

Validity and accuracy of regional bioelectrical impedance devices to determine whole-body fatness.

OBJECTIVE: Growing emphasis on obesity as a risk factor for chronic diseases and commercial availability of impedance devices for the at-home assessment of body fatness have stimulated the need for a critical evaluation of the validity of these instruments. This study determined the reproducibility and accuracy of two commercial impedance devices that use upper (hand-to-hand) or lower (foot-to-foot) body contact electrode placements in adults with a wide range of body fatness. METHODS: Body composition was assessed with dual x-ray absorptiometry in apparently healthy adults (62 women and 48 men) ages 21 to 60 y, with a range in body mass index of 18.6 to 40.5 kg/m2. Variability in body fatness predicted with the regional body impedance devices was determined in 10 adults on 5 consecutive d. A 50-kHz, tetrapolar bioelectrical impedance plethysmograph with surface electrode placements on the upper and lower limbs was used to determine reference regional and whole-body impedance values. RESULTS: Variability in body mass (1%) over 5 d was less than body fatness predicted with the upper (2-10%) and lower (3-5%) body devices. Regional and whole-body impedance values were different (P < 0.05) in the women, whereas upper and lower body values were lower (P < 0.05) than whole-body impedance in the men. Dual x-ray absorptiometric determinations of body fatness were similar to predictions based on models derived from physical characteristics (age, stature, body mass, and sex) but significantly different (P < 0.05) from estimates from the impedance devices, which underestimated body fatness. Bias in predictions of body fatness with the regional devices was systematically (P < 0.0001) related to body fatness. CONCLUSION: Use of regional impedance devices to assess body fatness is limited by a lack of precision and accuracy.

Induction of specific antitumor immunity in the mouse with the electrofusion product of tumor cells and dendritic cells.

Dendritic cells (DCs) are potent antigen-presenting cells capable of inducing primary T-cell responses. Several immunotherapy treatment strategies involve manipulation of DCs, both in vivo and ex vivo, to promote the immunogenic presentation of tumor-associated antigens. In this study, an electrofusion protocol was developed to induce fusion between tumor cells and allogeneic bone marrow-derived DCs. Preimmunization with irradiated electrofusion product was found to provide partial to complete protection from tumor challenge in the murine Renca renal cell carcinoma model and the B16 and M3 melanoma models. Vaccinated survivors developed specific immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. Antitumor protection in the B16 model was accompanied by the development of a polyclonal cytotoxic T-lymphocyte response against defined melanoma-associated antigens. The therapeutic potential of this type of approach was suggested by the ability of a Renca-DC electrofusion product to induce tumor rejection in a substantial percentage of hosts (60%) bearing pre-established tumor cells. These results indicate that treatment with electrofused tumor cells and allogeneic DCs is capable of inducing a potent antitumor response and could conceivably be applied to a wide range of cancer indications for which tumor-associated antigens have not been identified.

Tumor treatment with complexes of cationic lipid and noncoding plasmid DNA results in the induction of cytotoxic T cells and systemic tumor elimination.

We have demonstrated recently that treatment of established peritoneal mesothelial tumors with complexes composed of cationic lipid and noncoding plasmid DNA (pNull) results in the inhibition of tumor growth accompanied by the induction of a tumor-specific cellular immune response. In this study, treatment of mice bearing intraperitoneal (i.p.) M3 melanoma tumors with i.p. injections of lipid/pNull complex was found to inhibit tumor growth and induce the development of a cytolytic response against several M3 melanoma-associated antigens. Depletion of CD8(+) T cells, as opposed to natural killer (NK) or CD4(+) T cells, essentially abrogated the therapeutic effect of lipid+pNull complex, thus supporting the involvement of cytotoxic CD8(+) T cells in the antitumor response. The antitumor effect of lipid/pNull complex was maximal following delivery into a tumor-bearing compartment. For example, i.p. delivery of complex was more effective than intravenous (i.v.) or subcutaneous (s.c.) treatment of i.p. M3 tumors. In addition, i.v. injection of complex displayed therapeutic activity against lung metastases caused by i.v. injection of tumor cells, and intratumoral injection of complex into solid s.c. tumors caused regression in most animals. Importantly, the immune response induced by local treatment of tumors with complex also offered systemic protection against tumor cells at distal sites, as illustrated by the eradication of both peritoneal tumors and lung metastases in mice treated with complex delivered i.p. Treatment with lipid/pNull complex, therefore, represents an attractive immune-based treatment modality that could potentially be applied to many tumor types.

Association of dominant somatotype of men with body structure, function during exercise, and nutritional assessment.

This study examined the hypothesis that somatotype determines body structure, functional responses at peak exercise, and nutritional status of 63 men ages 18-40 years who lived under controlled conditions. Data were grouped by dominant somatotype to emphasize differences in body types. Dominant ectomorphs (n = 19) had less (P < 0.05) body weight, fat weight, and percent body fat than endomorphs (n = 14) and mesomorphs (n = 30). Fat-free weight (FFW), total body potassium (TBK), and body cell mass (BCM), normalized for stature, were lower (P < 0.05) in the ectomorphs than in the endomorphs and mesomorphs. Comparisons between measured and predicted FFW and TBK showed that only the ectomorphs had less (P < 0.05) FFW and TBK than expected. Although all groups had the same peak power output, the ectomorphs had different functional responses during peak exercise. Ectomorphs had the greatest respiratory exchange ratio (P < 0.05), ventilatory equivalent for oxygen, and end-exercise plasma lactate concentrations (P < 0.05), and lowest peak oxygen uptake (L/min; P < 0.05). Nutrient intakes and blood biochemical markers of nutritional status were within the range of normal values in all groups. Correlations between measures of body structure, function, and nutritional status and dominant somatotype components were calculated after controlling for the effects of the other two somatotype components. Partial correlations were variable, with significant correlations ranging from -0.30 to 0.87. These data indicate that ectomorphs, as compared to endomorphs and mesomorphs, have deficits in FFW and BCM which are associated with differences in functional capacity. Am. J. Hum. Biol. 12:167-180, 2000. Published 2000 Wiley-Liss, Inc.