Search

Background: Genital infection with certain strains of human papillomavirus (HPV) is associated with a high risk of malignant transformation, and HPV-associated cervical intraepithelial neoplasia (CIN) can become invasive cancer. Host factors are critical in regulating tumor growth, and cytokines that modulate immunologic control may be of particular importance. The type 1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are immunostimulatory and are thus capable of limiting tumor growth. The type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are immunoinhibitory and are thus capable of stimulating tumor growth.Purpose: We analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) in women with CIN associated with localized or extensively spread HPV infection.Methods: Thirty women diagnosed with CIN and 10 age- and sex-matched healthy control subjects were enrolled in the study conducted at Istituto Nazionale Tumori, Milan, Italy. The following parameters were analyzed: 1) HPV infection of the cervix and other sites of the lower genital tract by colposcopic, cytologic, and histologic examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in response to stimulation with soluble antigen (influenza [FLU] antigen) or to cell-associated human leukocyte antigen (HLA) alloantigen; and 4) in vitro production of the type 1 cytokines IL-2 and IFN gamma and of the type 2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation. Statistical significance was determined by nonparametric tests (two-sided).Results: High-grade CIN associated with HPV infection was detected in all case patients, and HPV type 16 or 18 infection was detected in cervical tissue of 21 (70%) of 30 case patients. HPV infection that had spread to other sites of the lower genital tract, thus resulting in more extensive disease, was detected in 16 (53%) of the 30 individuals with CIN, whereas HPV infection was limited to the portio in 14 (47%). IL-2 production by PBMCs in response to stimulation with soluble antigen or HLA alloantigen was reduced in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. In contrast, IL-4 and IL-10 production in response to mitogen stimulation was elevated in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. The highest production of IL-4 and IL-10 was detected in patients with HPV infection that had extended beyond the genital tract.Conclusions: CIN is characterized by different immunologic profiles, in which HPV infection is or is not confined to the portio. Production of cytokines that mainly enhance potentially protective cell-mediated immunity is defective in the women in whom extended HPV infection was observed. A pronounced shift from type 1 to type 2 cytokine production is associated with more extensive HPV infection.Implications: These data reinforce the need for detailed analyses of immune dysregulation in CIN patients. They also suggest the potential usefulness of the cytokine assays for determining prognosis or deciding whether cytokine-based therapy is indicated. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of primary aldosteronism (PA) is comprehensive, which includes case-detection testing, case confirmation followed by subtype classification. In certain instances, such as in the setting of spontaneous hypokalemia, suppressed renin activity (PRA) plus plasma aldosterone concentration (PAC) of > 15 ng/dL, one may not proceed with confirmatory tests. However, the quality of evidence behind this approach is very low. This study sought to evaluate the proposed "simplified confirmatory pathway" that can spare confirmatory testing for primary aldosteronism by evaluating the diagnostic performances of the various pre-specified PAC thresholds in combination with findings of suppressed renin and spontaneous hypokalemia., Methods: This is a multi-center, retrospective diagnostic accuracy cohort-selected cross-sectional study. A total of 133 participants aged 18 years and above underwent saline infusion test between January 2010 to March 2024. The outcome measures comprise of the diagnostic performances of the different index test combinations (baseline PAC, baseline PRA and presence of spontaneous hypokalemia): sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, negative likelihood ratio, and diagnostic accuracy. Data analysis was performed using SPSS 29.0.1.0 & MedCalc 20.218., Results: Of the 133 patients who underwent saline infusion test, 88 (66.17%) were diagnosed with PA. A PAC of > 25 ng/dL plus PRA < 1.0 ng/dL/hr with spontaneous hypokalemia showed the highest specificity at 100% (95% CI 90.51%, 100.00%) and positive predictive value at 100% (85.18 - 100.00%). The minimum acceptable combination criteria were determined to be a PAC of > 20 ng/dL plus PRA < 0.6 ng/dL/hr, and presence of spontaneous hypokalemia. It has high specificity (94.59%; 95% CI 81.81%, 99.34%), positive predictive value (93.55%, 95% CI 78.49%, 98.29%), and moderate positive likelihood ratio (LR+) (6.39, 95% CI 1.61, 25.38) CONCLUSION: A hypertensive patient with spontaneous hypokalemia and screening findings of PAC > 20 ng/dL and suppressed PRA of < 0.6 ng/ml/hr, may be classified as "overt primary aldosteronism confirmed" and may not need to proceed with dynamic confirmatory testing., Protocol Registration Number: SRCTN34186253., (© 2024. The Author(s).)

Background: Il Paese Ritrovato is an Italian nursing home founded in 2018, it is based on the Alzheimer village model and admits people with mild-to-moderate dementia., Objective: Describe the impact of the SARS-CoV-2 pandemic on people living at Il Paese Ritrovato through a Comprehensive Geriatric Assessment (CGA) regularly administered prior to and during the pandemic., Methods: We explored the effects of a person-centered approach. We assessed 64 subjects (enrolled and followed between June 2018 and December 2020), who underwent at least 18 months of observation prior to the pandemic. Each subject was evaluated using a CGA on admission time (T0) and at defined time-points: T6, T12, T18. One last CGA evaluation was performed during the SARS-CoV-2 pandemic (TCovid-19). Temporal trends during T0-T18, and differences between T18 and TCovid-19 were calculated., Results: The mean age was 82 years with a prevalence for females (77.0%) and Alzheimer's disease diagnosis (60%). Psychiatric and behavioral disorders were the most common conditions (80%). We utilized a nonpharmacological approach aimed at promoting the residents' overall wellbeing and observed satisfactory performance during the first 18 months. In comparison with the pre-pandemic period, TCovid-19 enlightened +11.7% use of antidepressants and a decline of Mini-Mental State Examination mean values (not statistically significant), while engagement in activities dropped., Conclusions: The pandemic may have disrupted the existing model of care, but at the same time, it confirmed that the Il Paese Ritrovato approach, which encompasses symptoms improvement and multicomponent support, is in fact beneficial.

Background: Albumin, along with other proteins, is abnormally eliminated via the urine during early stages of diabetic nephropathy. Moreover, endothelial dysfunction (ED) accompanying early diabetic nephropathy may develop even before microalbuminuria is detectable. Transferrin has a molecular weight comparable to albumin, whereas transferrinuria and microalbuminuria in a 24-h urine sample may comparably reflect early diabetic nephropathy. Whereas transferrin metabolism is related with ED during very early diabetic nephropathy has not been elucidated yet. This case-control study aimed to evaluate the relation between ED and urine transferrin, even before early diabetic nephropathy is present., Methods: Patients were enrolled from two study sites in Mexico City: Ticomán General Hospital (healthy controls); and a Specialized Clinic for the Management of the Diabetic Patient (cases). All patients provided written informed consent. The primary endpoint was the correlation between urinary transferrin concentration and ED measured in type 2 diabetic patients without albuminuria. ED was evaluated by ultrasonographic validated measurements, which included carotid intima-media thickness (CIMT) and flow mediated dilation (FMD). Plasma biomarkers included glycated hemoglobin, creatinine, cholesterol and triglycerides, as well as urine albumin, transferrin and evidence of urinary tract infection., Results: Sixty patients with type 2 Diabetes Mellitus (t2DM; n = 30) or without t2DM (n = 30), both negative for microalbuminuria, were recruited. The group with t2DM were older, with higher values of HbA1c and higher ED. This group also showed significant differences in urine transferrin and urine/plasma transferrin ratio, as compared with healthy controls (14.4 vs. 18.7 mg/mL, p = 0.04, and 74.2 vs. 49.5; p = 0.01; respectively). Moreover, urine transferrin correlated with higher CIMT values (r = 0.37, p = 0.04), being particularly significant for t2DM population. CIMT also correlated with time from t2DM diagnosis (r = 0.48, p < 0.001) and HbA1c (r = 0.48; p < 0.001)., Conclusion: Urine transferrin correlated with subclinical atherogenesis in patients with t2DM without renal failure, suggesting its potential to identify cardiovascular risk in patients at very early nephropathy stage without microalbuminuria., (© 2021. The Author(s).)

Classic Kaposi's sarcoma (cKS) is a human herpesvirus-8 (HHV-8)-associated lympho-angioproliferative tumor typically occurring in the elderly. It is associated with HHV-8-driven perturbed balance of peripheral B-cell subsets, which may have an impact on immune responses to antigenic stimulation. We took advantage of the common practice of cKS patients to undergo seasonal influenza vaccination because of advanced age and analyzed the immunogenicity and safety of licensed trivalent influenza vaccine in 46 cKS patients and 44 matched controls. Licensure criteria for immunogenicity were fulfilled in both groups. Four weeks after vaccination, hemagglutination-inhibition antibody titers against each viral strain contained in the vaccine increased in patients and controls (all P<0.001). Protection against at least one strain was achieved by 96% of cKS and 91% of control subjects. Protection against all strains persisted after 12 weeks, demonstrating a long-lasting response to vaccination. The vaccine was equally well tolerated by patients and controls, as assessed by evaluating solicited local and systemic reactions to the vaccine, and appearance or increase of antinuclear autoantibodies. HHV-8 virological rebound was observed in four cKS patients, but was not accompanied by progression of KS lesions. We conclude that seasonal influenza vaccine given to cKS patients is immunogenic and safe.

There are hints that hypoxia exposure may affect the number of circulating endothelial progenitor cells (EPCs) in humans. To test this hypothesis, the concentration of EPCs was determined by flow cytometry in the peripheral blood of 10 young healthy adults before (0 h), at different times (0.5 h, 1 h, 2 h and 4 h) during a 4 h normobaric hypoxic breathing simulating 4100 m altitude, and in the following recovery breathing room air. Results were interpreted mainly on the basis of the changes in surface expression of CXC chemokine receptor-4 (CXCR-4, a chemokine receptor essential for EPC migration and homing) and the percentage of apoptotic cells, the plasmatic levels of markers of oxidative stress induced by hypoxic breathing. Compared to 0 h, the concentration of EPCs, identified as either CD45(dim)/CD34(+)/KDR(+) or CD45(dim)/CD34(+)/KDR(+)/CD133(+) cells, decreased from 337 ± 83 ml(-1) (mean ± SEM) to 223 ± 52 ml(-1) (0.5 h; P < 0.005) and 100 ± 37 ml(-1) (4 h; P < 0.005), and from 216 ± 91 to 161 ± 50 ml(-1) (0.5 h; P < 0.05) and 45 ± 23 ml(-1) (4 h; P < 0.005), respectively. Upon return to normoxia, their concentration increased slowly, and after 4 h was still lower than at 0 h (P < 0.05). During hypoxia, CXCR-4 expression and plasmatic stromal derived cell factor-1 (SDF-1) increased abruptly (0.5 h: +126% and +13%, respectively; P < 0.05), suggesting cell marginalization as a possible cause of the rapid hypoxia-induced EPC reduction. Moreover, hypoxia exposure induced an increase in EPC apoptosis and markers of oxidative stress, which was significantly evident only starting from 2 h and 4 h after hypoxia offset, respectively, suggesting that EPC apoptosis may contribute to the later phase of hypoxia-induced EPC reduction. Overall, these observations may provide new insights into the understanding of the mechanisms operated by EPCs to maintain endothelial homeostasis.

Successful pregnancy relies on the adaptation of immune responses that allow the fetus to grow and develop in the uterus despite being recognized by maternal immune cells. Dendritic cells (DCs) are central to the control of immune tolerance, and their state of activation at the maternal-decidual interface is critical to the feto-maternal immunological equilibrium. So far, the involvement of circulating DCs has been investigated poorly. Therefore, in this study we investigated whether, during healthy human pregnancy, peripheral blood DCs (PBDCs) undergo changes that may be relevant to the adaptation of maternal immune responses that allow fetal tolerance. In a cross-sectional study, we analysed PBDCs by six-colour flow cytometry on whole blood samples from 47 women during healthy pregnancy progression and 24 non-pregnant controls. We demonstrated that both myeloid and plasmacytoid PBDCs undergo a state of incomplete activation, more evident in the third trimester, characterized by increased expression of co-stimulatory molecules and cytokine production but lacking human leucocyte antigen (HLA)-DR up-regulation. To investigate the contribution of soluble circulating factors to this phenomenon, we also performed culture experiments showing that sera from pregnant women added to control DCs conditioned a similar incomplete activation that was associated with reduced DC allostimulatory capacity, supporting the in vivo relevance of our findings. We also obtained evidence that the glycoprotein hormone activin-A may contribute to DC incomplete activation. We suggest that the changes of PBDCs occurring during late pregnancy may aid the comprehension of the immune mechanisms operated by the maternal immune system to maintain fetal tolerance., (© 2011 The Authors; Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Background: Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS) and of some lymphoproliferative disorders of B cells. Most malignancies develop after long-lasting viral dormancy, and a preventing role for both humoral and cellular immune control is suggested by the high frequency of these pathologies in immunosuppressed patients. B cells, macrophages and dendritic cells of peripheral lymphoid organs and blood represent the major reservoir of HHV-8. Due to the dual role of B cells in HHV-8 infection, both as virus reservoir and as agents of humoral immune control, we analyzed the subset distribution and the functional state of peripheral blood B cells in HHV-8-infected individuals with and without cKS., Methodology/principal Findings: Circulating B cells and their subsets were analyzed by 6-color flow cytometry in the following groups: 1- patients HHV-8 positive with classic KS (cKS) (n = 47); 2- subjects HHV-8 positive and cKS negative (HSP) (n = 10); 3- healthy controls, HHV-8 negative and cKS negative (HC) (n = 43). The number of B cells belonging to the preimmune/natural effector compartment, including transitional, pre-naïve, naïve and MZ-like subsets, was significantly higher among HHV-8 positive subjects, with or without cKS, while was comparable to healthy controls in the antigen-experienced T-cell dependent compartment. The increased number of preimmune/natural effector B cells was associated with increased resistance to spontaneous apoptosis, while it did not correlate with HHV-8 viral load., Conclusions/significance: Our results indicate that long-lasting HHV-8 infection promotes an imbalance in peripheral B cell subsets, perturbing the equilibrium between earlier and later steps of maturation and activation processes. This observation may broaden our understanding of the complex interplay between viral and immune factors leading HHV-8-infected individuals to develop HHV-8-associated malignancies.

Restoring blood flow to ischemic tissue is a prerequisite for treatment of ischemic diseases. Cell-based therapy based on bone marrow transplantation is a promising option for patients with critical limb ischemia (CLI). The efficacy of cell therapies to augment neovascularization seems to involve endothelial progenitor cells (EPCs); however, the mechanisms underlying the efficacy have not been fully elucidated. Herein we have described the case of a young patient with severe CLI, who experienced a 24-month beneficial clinical response to autologous bone marrow transplantation. The exceptional amelioration enabled him to perform standardized maximal treadmill exercise test that demonstrated lack of exercise-induced EPC mobilization, despite adequate stromal-derived factor 1 and vascular endothelial growth factor responses. Therefore, tissue ischemia is not sufficient to promote the recruitment of EPCs that have been demonstrated to be involved in the recovery from ischemia. The local implantation of marrow-derived elements may provide cells and/or trophic factors, which have the capacity to augment angiogenesis, opening new approaches to the etiopathogenesis of the disease., (2010 Elsevier Inc. All rights reserved.)

Defensins are endogenous defense peptides with well defined antimicrobial activity against a broad spectrum of pathogens including bacteria, fungi, viruses, and parasites.Several lines of evidence suggest that defensins might also contribute to the regulation of host innate and adaptive immunity, but their immunomodulatory functions are still poorly understood. Herein, we studied the impact of human defensins on multiple functions of DCs, which are a central player in all immune responses, bridging innate and adaptive immunity. We challenged DCs differentiated in vitro from human moDCs with HNP-1 alpha-defensin or HBD-1. HNP-1 and HBD-1 were chemotactic for moDCs. Both defensins promoted the activation and maturation of moDCs, as assessed by up-regulation of surface expression of the costimulatory molecules CD80, CD86, and CD40, the maturation marker CD83, and HLA-DR. HNP-1 and HBD-1 also enhanced the production of the proinflammatory cytokines TNF-alpha, IL-6, and IL-12p70 but did not affect the production of the regulatory cytokine IL-10. According to these stimulatory effects, HNP-1 and HBD-1 increased the allostimulatory activity of moDCs significantly. Finally, HNP-1 and HBD-1 promoted the up-regulation of CD91 on the DC surface. CD91 is a scavenger receptor involved in the recognition of multiple ligands including defensins, thus suggesting that defensins may amplify their own effects through the activation of an autocrine loop. Taken together, our observations may provide new insight into the immunomodulatory properties of human defensins and may aid the exploration of new therapeutic strategies to potentiate antimicrobial and antitumor immunity.

Analysis of peripheral blood dendritic cells (PBDCs) is increasingly reaching clinical relevance in a wide range of pathologies, in which investigating the capacity of DC subsets to respond adequately to specific stimuli may aid the comprehension of underlying immunopathologic mechanisms. The evaluation of PBDC responses directly challenged in whole blood (WB) samples offers many advantages over other methods that require DC isolation and culture, but it is limited in multiparametric analysis, currently based on 3- or 4-color assays. Therefore, in this study we developed a 6-color assay dedicated to the analysis of PBDC responses upon WB stimulation. We incubated WB samples with ligands to toll-like receptors (TLRs) with a clear-cut distribution on myeloid DCs (mDCs) or plasmacytoid (pDCs) and analyzed DC responses in terms of upregulation of activation/maturation markers, as well as production of a wide range of regulatory cytokines. Four colors were used to gate on mDCs and pDCs that were identified as lineage-/HLA-DR+/CD11c+ and lineage-/HLA-DR+/CD123+, respectively, and two further colors were used to analyze either the surface expression of CD80, CD86, CD40 or CD83, or the intracellular accumulation of IL-12, tumor-necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IL-6, IL-10 or IL-4. With this method, we could directly compare in the same flow cytometric tube the responses of mDCs and pDCs to TLR stimulation, and investigate the reciprocal coexpression of distinct activation markers or regulatory cytokines. We suggest that the 6-color WB assay presented here may represent a novel tool for investigating the complex biology of DCs.

Background: Flow cytometric analysis of peripheral blood dendritic cells (PBDCs) and their myeloid (mDCs) and plasmacytoid (pDCs) subsets is a less invasive procedure that is acquiring growing clinical relevance. Because dendritic cells (DCs) lack unique lineage markers, current methods that are based on 3- or 4-color assays do not allow multiparametric analysis of DC subsets. In this study a dedicated 6-color assay was developed., Methods: mDCs and pDCs were counted and characterized for the expression of activation/maturation markers by using a single-platform 6-color assay. Whole-blood samples from 20 healthy controls were directly stained with either CD80-FITC/CD40-PE/lineage-PerCP-Cy5.5/CD123-PE-Cy7/CD11c-APC/HLA-DR-APC-Cy7 or CD86-FITC/CD83-PE/lineage-PerCP-Cy5.5/CD123-PE-Cy7/CD11c-APC/HLA-DR-APC-Cy7 combination, in the presence of commercial fluorospheres. A dual-platform 3-color assay currently in use was run in parallel for comparison., Results: The 6-color assay provided mDCs and pDCs counts similar to counts obtained by the 3-color assay. Only the 6-color assay could show differential expression of activation markers by mDCs and pDCs, with pDCs expressing lower levels of costimulatory molecules and HLA-DR, but higher levels of CD83., Conclusions: The 6-color assay described here may be a sensitive tool for assessing possible variations in the number and features of mDCs and pDCs whose reciprocal balance is critical in understanding the more detailed orchestration of immune responses.

Keyhole limpet hemocyanin (KLH) is a xenoantigen largely used in vitro as an immunogen to study primary antigen-specific T cell responses and in vivo as a vaccine component with optimal carrier qualities. So far, the mechanisms by which KLH exerts its immunostimulatory properties are still largely unknown. In particular, although dendritic cells (DCs) play a central role in the initiation and activation of immune responses, the effects of KLH on these cells have been poorly explored. In the present study we investigated the effects of KLH on DCs differentiated in vitro from human monocytes. We observed that KLH promotes the activation and maturation of DCs, as assessed by up-regulation of the surface expression of CD80, CD86, CD40, HLA-DR and CD83. Moreover, even if KLH stimulated the production of IL-12 and IL-10 by DCs, the final balance was clearly in favour of IL-12. According to these stimulatory effects, KLH significantly increased the allostimulatory activity of DCs. To verify whether these effects of KLH may be related to the binding of this highly glycosilated molecule to mannose receptor (MR), we performed inhibition experiments with anti-MR antibody. Results showed that the stimulatory activity of KLH is indeed partially mediated by its interaction with MR. Taken together, our results seem to indicate that KLH does promote the maturation of DCs endowed with the ability to stimulate cell-mediated immune responses. We suggest that this property of KLH may represent a novel further mechanism by which this molecule may exert its efficacy when co-administered with others antigens in immunotherapeutic protocols.

Background: The cellular reservoirs of Kaposi's sarcoma-associated herpesvirus (KSHV) and the exact nature of the putative KSHV-infected circulating precursor of spindle cells of Kaposi's sarcoma (KS) still remain poorly defined. Because KS spindle cells are thought to be of endothelial origin, and because mature endothelial cells do not sustain persistent KSHV-infection, our attention was focalized on circulating hematopoietic precursors able to differentiate into endothelial lineage., Methods and Findings: Late endothelial progenitor cells (late-EPCs) were cultured from the peripheral blood mononuclear cells of 16 patients with classic KS. The presence and load of KSHV genomes were analyzed by real-time polymerase chain reaction in DNA extracted from cells and supernatants of late-EPC cultures obtained from 7 patients. Endothelial colonies cultured from the peripheral blood of KS patients were found to satisfy all requisites to be defined late-EPCs: they appeared from the CD14-negative fraction of adherent cells after 11-26 days of culture, could be serially expanded in vitro, expressed high levels of endothelial antigens but lacked leukocyte markers. Late-EPC cultures were found to harbor KSHV-DNA at variable levels and to retain the virus after multiple passages in cells as well as in supernatants, suggesting that a quote of KSHV lytic infection may spontaneously occur. Lytic phase induction or hypoxia could amplify virus release in supernatants., Conclusion: Our results suggest that circulating endothelial progenitors from KS patients are KSHV-infected and support viral productive replication and may therefore represent potential virus reservoirs and putative precursors of KS spindle cells.

Through the production of stimulatory and suppressive cytokines, dendritic cells (DCs) regulate virus-specific immune responses that are crucial to virus eradication. To explore a possible role of DCs in the persistence of hepatitis C virus (HCV) infection, in this study we analysed peripheral blood DCs (PBDCs) in patients with chronic hepatitis C (CHC) compared with those in both healthy seronegative (HSN) controls and a group of subjects who had spontaneously resolved infection, defined as healthy HCV-seropositive (HSP), and we evaluated the relationships between PBDCs and HCV-specific CD4(+) T-cell reactivity. The number of PBDCs, their immunophenotype and expression of regulatory cytokines were evaluated by flow cytometry on whole-blood samples. HCV-specific CD4(+) T-cell activation, proliferation and cytokine production were evaluated in cultures of peripheral blood mononuclear cells (PBMCs) stimulated in vitro with HCV peptides. We found that PBDCs from CHC subjects were numerically reduced and showed lower interleukin-12 (IL-12) and higher IL-10 expression than those from HSN controls. PBDCs from HSP subjects were similar to those from HSN controls. HCV-specific CD4(+) T-cell proliferation was less frequent and vigorous in CHC than in HSP patients and was directly related to the number of PBDCs and their IL-12 production but inversely related to their IL-10 production. Taken together, these results seem to suggest that cytokines of DC origin contribute to the regulation of HCV-specific immunity in CHC patients and indicate that PBDCs may represent a novel non-invasive tool for immune monitoring of these patients.

Although the immune system is clearly capable of recognizing and eliminating tumor cells, it usually fails to provide adequate protective antitumor responses. It is becoming increasingly clear that modifications of dendritic cells (DCs), which are central regulators of immune responses, could be a strategy exploited by tumor cells to escape from immune control. This review focuses on the current understanding of DC defects occurring in cancer patients, mechanisms responsible for the induction of such defects, consequences of DC defects on antitumor immune response and current concepts of DC-based immunotherapy. An improved understanding of how tumors interact with DCs to escape from immune control may enable the design of improved DC-based immunotherapeutic strategies for patients with cancer.

Dendritic cells (DCs) are the single most central player in all immune responses. To assess whether DC alterations may contribute to the immune dysregulation that affects the elderly, we investigated the effects of ageing on DCs. We analyzed the number, phenotype and function of peripheral blood DCs from 70 healthy subjects aged 20-92 years by using flow cytometric methods that allow cell characterization directly in whole blood samples. We demonstrated that the number of myeloid DCs progressively declines with age. This finding was accompanied by a decrease of CD34+ precursors and increase of circulating monocytes, suggesting that the entire differentiation process of antigen presenting cells is partially dysregulated in the elderly. DCs from aged individuals also appeared to have a more mature phenotype and impaired ability to produce IL-12 upon stimulation. These results may help to clarify the contribution of innate immunity to the development of immunosenescence.

Activation-induced cytidine deaminase (AID), an enzyme with homology to members of the APOBEC family, is involved in somatic hypermutation (SHM) of immunoglobulin (Ig) genes, either by direct deamination of DNA or by an indirect action through its putative RNA editing activity. AID is able to mutate both Ig-like reporter constructs and selected non-Ig genes in normal B cells and in other cells when ectopically overexpressed in mammalian cells and transgenic mice. However, in spite of the fact that in these transgenic animals AID activity was driven by an ubiquitous promoter, only T lymphomas and lung adenomas occurred. In the present work, we constructed three sets of transgenic mice in which AID was under the control of lck, HTLV-I and MMTV promoters, respectively. The lck/AID mice developed thymic lymphomas with variable but high efficiency, while no tumor was detected in HTLV-I/AID mice after two years of monitoring. Four MMTV/AID founder mice died with an atypical clinical picture, although no mammary tumor was found. These findings suggest that additional factors, present in thymocytes but not in other tissues or in lymphoid cells at different stages of differentiation, are needed for AID to fully manifest its tumorigenic potential in mouse. Alternatively, the display of full AID mutagenic and transforming activity could be related to the existence of physiologic DSBs which occur in both thymocytes and switching B cells.

In this study, we investigated whether dendritic cells (DCs) are altered in classic Kaposi's sarcoma (cKS), a lympho-angioproliferative disorder associated with human herpesvirus-8 (HHV-8) infection. By direct analysis of peripheral blood DCs (PBDCs), we demonstrated that cKS patients have lower frequency of myeloid and plasmacytoid DCs than controls. This reduction was greater in patients with advanced stages of disease. PBDCs from cKS patients also showed up-regulated expression of the scavenger receptor CD91 and impaired IL-12 expression. PB monocytes that represent DC precursors in vivo and in vitro showed the same alterations; accordingly, DCs differentiated in vitro from cKS monocytes were similarly affected. The same alterations were induced by addition of cKS plasma during DC differentiation from control monocytes. These results indicate that PBDCs and their precursors are altered in cKS and suggest that soluble circulating factors participate in this process. The study may provide new insights into the pathogenesis of cKS.

Background/aims: T-lymphocyte reactivity against viral antigens may represent the only immunological marker of host contact with a virus. Aim of the present study was to investigate whether vertical exposure to hepatitis C virus (HCV) could activate HCV-specific T-cell responses that may represent a biomarker of previous contact with the virus, and possibly contribute to the low rate of vertical HCV transmission., Methods: We studied 28 children born from chronically HCV-infected mothers. HCV-specific activation and proliferation of CD4+-lymphocytes and cytokine production were evaluated in cultures of peripheral blood mononuclear cells (PBMCs) stimulated in vitro with HCV-peptides., Results: HCV-specific CD4+-cell reactivity was observed in 20 out of the 28 children (71%). The proliferation of HCV-specific CD4+-cells was more frequent and vigorous in children than in their mothers. In children, but not in the mothers, activation of CD4+-cells upon stimulation with HCV-peptides was directly correlated with proliferation. Early upon stimulation with HCV-peptides, lymphocytes from children produced lower levels of IL-10 than lymphocytes from the mothers., Conclusions: Vertical exposure to HCV induces the development of viral-specific CD4+-cell-mediated immune responses, possibly endowed with protective function against infection, which may contribute to the low rate of vertical HCV transmission.

Comparison between current and premorbid memory ability may be of help when trying to make a timely diagnosis of cognitive decline in questionable dementia. In the present study, we evaluated the possibility of estimating episodic verbal memory scores at the Rey Auditory Verbal Learning Test (RAVLT) from an irregular words reading task held to resist to deterioration, that is the Italian analogue of the NART, the TIB (Test d'Intelligenza Breve--brief intelligence test). A regression analysis was performed in a large sample of healthy elderly, using RAVLT scores as dependent variable and TIB score, MMSE score, age and education as predictors. We failed to find a relationship between the two tests that was strong enough for a reliable estimation of memory ability.

The Frontal Assessment Battery (FAB) is a short cognitive and behavioural six-subtest battery for the bedside screening of a global executive dysfunction; although recently devised, it is already extensively used thanks to its ease of administration and claimed sensitivity. The aim of the present study was to derive Italian normative values from a sample of 364 control subjects (215 women and 149 men) of different ages (mean: 57.4+/-17.9 years; range: 20-94 years) and educational level (mean: 10.4+/-4.3 years; range: 1-17 years); the Mini Mental State Examination (MMSE) was concurrently administered. Multiple linear regression analysis revealed significant effects for age and education whereas gender was not significant; thus, from the derived linear equation, a correction grid for FAB raw scores was built. Based on nonparametric techniques, inferential cut-off scores were subsequently determined and equivalent scores (ES) computed. Test-restest and interrater reliabilities were both satisfactory. Interestingly, MMSE was significantly correlated with FAB raw scores, whereas adjusted scores were not. The present data may improve the accuracy in the use of the FAB both for clinical and research purposes.

Background: Repeated exposure to HIV is not always associated with infection and multiple cohorts of HIV-exposed but seronegative individuals (ESN) have been described. HIV-specific CD4 and CD8 T lymphocytes are detected both in HIV patients and in ESN; we verified whether different patterns of HIV-specific memory T lymphocytes would be detected in individuals in whom exposure to HIV results or does not result in infection., Methods: Gag-specific T cells were analysed in 15 ESN, 14 HIV patients, and 15 healthy controls using extensive flow cytometry analysis., Results: Data confirmed that gag-specific T lymphocytes are present in ESN. Gag-specific T cells mainly secrete interleukin-2 in ESN and interferon-gamma in HIV patients. In addition the CD4/CD8 and the memory/naive ratios are altered, central memory (45RA-/CCR7+) CD4 and CD8 T lymphocytes are more abundant, and terminally differentiated (45RA+/CCR7- and 27-/28-) CD8 T lymphocytes are augmented in ESN individuals., Conclusions: Exposure to HIV occurs in high risk seronegative individuals; the observation that naive cells and CM are skewed in ESN indicate that this exposure is robust enough to modulate the CM/EM ratio. The increase in late effectors and in natural killer cells seen in ESN suggests a role for these cells in preventing actual infection.

The effects of interleukin 16 (IL-16) on dendritic cell (DC) generation from human CD34(+) progenitor cells are not known. Here, we show that IL-16 added to a basal cocktail comprised of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4, Flt-3 ligand (Flt3L), and tumor necrosis factor alpha (TNF-alpha) does induce the CD34(+) hematopoietic cells to proliferate in vitro and to differentiate into phenotypically and functionally mature DCs. IL-16 exerts this function more efficiently than stem cell factor (SCF) as a control, thrombopoietin (TPO), or IL-16 plus TPO. Moreover, we show that the combination of IL-16 plus TPO induces the generation of tolerogenic DCs, able to induce an anergic state in T cells that persists when T cells are rechallenged with immunogenic DCs. An altered pattern of cytokine production, a reduced expression of the C-type lectin DC-SIGN, and an increased surface expression of the inhibitory molecules immunoglobulin-like transcript 2 (ILT-2), ILT-3, and ILT-4 may all contribute to confer the tolerogenic properties of these DCs. Generation of tolerogenic DCs may aid the exploration of new therapeutic strategies to promote tolerance to autoantigens and prevent disease development.

Objectives: Growth hormone (GH) plays a role in thymic function, and recombinant GH may stimulate thymopoiesis in HIV-infected individuals. We performed immunologic analyses in 26 antiretroviral-treated children matched for age, pubertal status, clinical parameters, and antiretroviral exposure who did or did not show an impaired response to GH-release stimulation tests with arginine + GH-releasing hormone., Results: The following abnormalities were found in GH-deficient compared with GH-nondeficient children after >4 years of therapy: CD4 count ( P = .02) and percentage ( P = .03), CD4 as percentage of normal cells for age ( P = .003), serum interleukin-7 concentration ( P = .02), and thymic volume ( P = .01). Naive CD4 (4+62+RA+ and 4+CCR7+RA+) and CD8 (8+CCR7+RA+) lymphocytes were lower in GH-deficient children ( P = .003; P = .007; and P = .02, respectively). Postthymic pathways were also impaired in GH-deficient children. Thus, central memory (4+CCR7+RA-) CD4+ cells were reduced ( P = .006), whereas effector memory (4+CCR7-RA-) CD4+ cells ( P = .002) and late effector CD8+ lymphocytes (8+CCR7-RA+ and 8+27-28-) ( P = .009 and P = .002, respectively) were increased in these children., Conclusions: Growth hormone plays a role in thymic and postthymic pathways, and defective GH production may be associated with incomplete immunoreconstitution. Immunomodulant agents (including GH) could be useful in patients with defective GH production.

Background: HIV-specific cytotoxic T-cell (CTL) responses are defective in HIV-infected patients undergoing antiretroviral therapy (ART). This defect has been attributed to the decreased antigenic burden secondary to ART-associated suppression of HIV-replication, and is responsible for the rebounds of viraemia that occur when patients interrupt therapy. CTL are stimulated by type 1 cytokines and can kill targets via granule-dependent (perforin and granzymes) and -independent (tumour necrosis factor-alpha, CD95) mechanisms., Methods: Granule-dependent and granule-independent mechanisms of CTL killing, as well as type 1 cytokine production by CD4 T cells, were analysed in 57 chronically HIV-infected ART-treated or ART-untreated individuals., Results: The results can be summarized as follows: the frequency of gp160 (env)-specific interferon-gamma-secreting CD8 T lymphocytes correlates positively with HIV viraemia in ART-treated and -untreated patients; Env-specific perforin- and granzymes-expressing CD8 T lymphocytes, and Env-stimulated perforin and granzymes mRNA, are reduced in ART-treated patients independently of HIV viral load and of type 1 cytokine production; tumour necrosis factor-alpha production is increased in ART-treated individuals; and Env-specific immature CD8+28+27+ cells are only marginally augmented in ART-treated patients, Similar results are observed in cytomegalovirus-specific CD8 T cells and peripheral blood mononuclear cells., Conclusions: A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.

Monocyte-derived dendritic cells (DCs) generated in granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4-DCs) are used to enhance antitumor immunity in cancer patients, although recent evidence suggests that their functional repertoire may be incomplete; in particular, IL-4-DCs appear unable to induce type 2 cytokine-producing T helper (Th) cells. To assess whether type 1 interferon (IFN) could replace IL-4 and generate DCs with a more complete repertoire, we characterized in detail DCs generated from human monocytes cultured with GM-CSF and IFN-alpha (IFN-DCs). We found that IFN-alpha induces DC differentiation more efficiently than IL-4, yielding similar numbers of DCs in a shorter time and that this differentiation persists upon removal of cytokines. Although IFN-DCs had a more mature immunophenotype than IL-4-DCs, showing higher expression of CD80, CD86, and CD83, they still preserved comparable endocytic and phagocytic capacities and responsiveness to maturation stimuli. IFN-DCs had strong antigen-presenting capacity, inducing intense proliferation of T cells to alloantigens or influenza virus. Moreover, IFN-DCs produced lower levels of IL-12p70 and higher levels of IFN-alpha, IL-4, and IL-10 than IL-4-DCs. As a consequence of this different pattern of cytokine secretion, IFN-DCs induced T cells to produce type 1 (IFN-gamma) and type 2 (IL-4 and IL-10) cytokines, and as expected, IL-4-DCs induced only Th1 differentiation. As immune responses with extreme Th1 bias are considered inadequate for the induction of optimal, systemic antitumor immunity, the ability of IFN-DCs to promote more balanced cytokine responses may suggest the advisability to consider these cells in the development of future, DC-based immunotherapy trials.

Aim: Kaposi's sarcoma (KS) is a lympho-angioproliferative disorder characterized by angiomatous nodules and plaques that mainly affect the skin. The disease is consistently associated with human herpesvirus-8 (HHV8) and with a state of preexistent immunosuppression. Dendritic cells (DCs) have an instrumental role in the activation and function of both innate and adaptative immune responses. At least 2 distinct subsets have been characterized in peripheral blood based on phenotypic markers: myeloid DCs (CD11c+), associated with Ag uptake, T cell activation and ability to secrete IL-12, and plasmacytoid DCs, high virus-induced IFN-alpha producing cells. Because of the role of both DC subtypes in antiviral and antitumor induced responses, we hypothesized that DCs could be involved in the onset and evolution of KS., Methods: Thirty-five patients with mediterranean KS assigned to different clinical stages were compared with 51 healthy control subjects. Peripheral blood DCs were quantified and functionally characterised by flow cytometry directly on whole blood samples. The production of the regulatory cytokines, IL-12 and IL-10, was assessed as intracellular accumulation after incubation with or without lipopolysaccharide (LPS)., Results: Myeloid DCs identified as lineage-/HLA-DR+/CD11c+ cells were significantly lower in KS patients than in controls (0.54+/-0.25 vs 0.69 +/-0.26% of the peripheral blood mononuclear cells; p<0.017). Furthermore, CD11c+ DCs were lower in patients with more diffuse disease. Plasmacytoid DCs, identified as lineage-/HLA-DR+/CD123+ cells, were lower in KS patients (0.23+/-0.19 vs 0.36+/-0.17; p<0.001). DCs from KS patients were more mature, as assessed by expression of the maturation marker CD83, and showed an impaired ability to produce IL-12 upon LPS stimulation, as compared with controls., Conclusion: The numerical and functional alterations of peripheral blood DCs observed in KS patients suggest an involvement of these cells in the onset and evolution of the disease.

Physiological age-related cognitive decline, practice effect and regression to the mean may interfere with the interpretation of psychometric changes between subsequent neuropsychological evaluations. The standardized regression-based (SRB) change score allows investigators to define clinically relevant cognitive change on an individual basis controlling for these confounding factors. We performed a preliminary study to test its applicability and usefulness in the neuropsychological diagnosis of dementia. We derived a regression equation for the tests of a widely used Italian battery for global cognitive assessment, the Mental Deterioration Battery, in a sample of 20 normal elderly and we tested the potential clinical application of the SRB methodology in two cases of questionable dementia.

Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P<0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P=0.016), and had impaired production of IL-12 (P<0.001). These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumour-related immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs.

The Time and Weight Estimation test (STEP) and the Cognitive Estimation Task (CET) are two recently devised tests for the assessment of cognitive estimation. In the present study, we compared their performance in 30 non-demented idiopathic parkinsonian (PD) patients, also evaluated with the Frontal Assessment Battery (FAB) as an index of executive impairment, with the aim of verifying the putative frontal circuitry of cognitive estimation processes. Six patients (20%) showed a pathological performance on either or both tests. After division of the PD sample into tertiles based on the FAB score, no significant difference was detected by either estimation test. Furthermore, the two questionnaires were unrelated to each other. Thus, deficits of cognitive estimation ability appear to be mild in PD without dementia and do not correlate with executive impairment. Unexpectedly, the CET and the STEP seem to have no unique underlying construct.

Background: Despite multiple, repeated exposures to HIV-1, some individuals never seroconvert. Mucosal and systemic immune correlates of this condition have been analysed in HIV-1-exposed women but no data are available concerning mucosal immunity and HIV-1-specific immune responses in exposed but uninfected men., Design: We analysed cellular and humoral immune parameters in peripheral lymphocytes, seminal fluid and urethral swabs of 14 recently HIV-1-exposed seonegative (ESN) heterosexual men, seven HIV-seropositive patients and seven healthy controls., Results: HIV-1-specific IgA were detected in urethral swabs of 11 out of 14 ESN and of six out of seven HIV-seropositive patients; Env- and Gag-specific IFNgamma-producing CD4 and CD8 peripheral lymphocytes were present in ESN and HIV-seropositive patients; seminal lymphocytes, but not peripheral blood lymphocytes, of ESN were enriched in activated populations (CD8CD38RO and CD4CD25). p24-specific cytotoxic T lymphocytes were correlated with the percentage of CD4 in the HIV-seropositive partners. High urethral concentrations of HIV-1-specific IgA were seen in those ESN with the most recent unprotected sexual episode., Conclusions: This is the first report of HIV-specific mucosal immunity in ESN men. These data add to the body of knowledge of the immune correlates present in exposed, uninfected individuals and might be important in vaccine design.

Introduction: Sarcoidosis is a multisystemic disease of unknown etiology, characterized by non caseating granulomas in different organs. The respiratory system is the most frequently involved organ system. Up to 90% of patients with sarcoidosis have pulmonary involvement. The neurological involvement is rare and only occurs in the 5 7% of the patients., Case Report: We present the case of a 41 years old woman who had severe headache and a sixth nerve palsy. Diagnosis of sarcoidosis was made in association with idiopathic intracranial hypertension (IIH)., Conclusions: Sarcoidosis can involve any portion of the nervous system. An etiologic association between sarcoidosis and IIH could be identified in this case. Treatment with corticosteroids, repeated lumbar punctures and diuretics were prescribed and induced a significant clinical improvement.

The IQCODE is a retrospective questionnaire for caregivers about changes which occurred in a patient's cognitive and functional efficiency in the previous 10 years of life. Previous studies demonstrated the validity of the IQCODE for the screening of dementia similar to that of traditional cognitive screening tests, with the additional advantage of allowing the detection of cognitive change, rather than just cognitive impairment. The present paper deals with the preliminary results of the validation of the Italian version of the questionnaire in a sample of 45 mild to severely demented patients and 13 patients with mild cognitive impairment (MCI), compared to 20 cognitively intact elderly subjects. The IQCODE demonstrated satisfactory discriminative power for dementia as well as for MCI and a good correlation with the MMSE.

Background: The immunologic characterization of chronic idiopathic urticaria (CIU) is still incomplete. In particular, it is not known if positivity to the intradermal autologous serum skin test (ASST) identifies an immunologic subset of CIU patients., Methods: Nineteen CIU patients and 15 healthy controls were enrolled in the study. A diagnostic flowchart was designed to select CIU patients, who were then analyzed by ASST. Cytokine and chemokine production and the expression of adhesion molecules was measured in patients and controls., Results: In CIU patients compared to controls, it was found that (1) TNF-alpha, IL-10, MIP-1alpha and RANTES production was augmented and IL-2 and INF-gamma reduced, and (2) CD44, CD11a and CD62L expression on CD4 and CD8 cells was augmented. Additionally, TNF-alpha and chemokine production was significantly increased in CIU patients with a negative ASST (p-; n = 10) compared to patients with a positive response to the test., Conclusions: The presence of an inflammatory process in CIU patients is suggested by the findings that the production of both TNF-alpha and chemokines as well as the expression of adhesion molecules is increased in these patients. Similarly to what is seen in rheumatoid arthritis, augmented IL-10 production might be secondary to the attempt to hamper the inflammatory milieu. Immune profiles are particularly altered in CIU p- patients, in whom a more aggressive therapeutic strategy might be considered., (Copyright 2002 S. Karger AG, Basel)

Setting: Urban and rural communities and urban poor settlements in the Philippines., Objective: To determine bacillary disease and action taking among individuals with symptoms of tuberculosis (TB), and to analyze their implications for TB control., Study Design and Method: Subjects aged 20 years and older were interviewed in the 1997 nationwide stratified multi-cluster survey. Sputum acid-fast smears and cultures were done in subjects with abnormal screening chest radiographs., Results: Individuals with TB symptoms comprised 18.1% of the population studied. The prevalence of bacillary disease was 39/1000 in symptomatic subjects compared to 13/1000 in asymptomatic subjects. Symptom screening had a 14.3% positive predictive value and a 91.4% negative predictive value for bacillary disease. Significantly more symptomatic than asymptomatic subjects attended chest radiographic screening during the survey. However, in response to their symptoms, the majority (43.0%) took no action or self medicated (31.6%), while 11.8% consulted a private practitioner, 7.5% a public health center, 4.4% a hospital, and 1.7% a traditional healer., Conclusion: Sputum smear examination after symptom screening was acceptable for case finding. The health seeking behavior of subjects with TB symptoms was inappropriate. A health education program and public-private collaboration in directly observed therapy, short course (DOTS) are essential for TB control in the Philippines.

Cell-mediated immunity and T-lymphocyte maturation are impaired in HIV-infected children. These abnormalities would be detected in HIV-uninfected offspring of HIV women (seroreverters [SR]) if HIV or its soluble proteins could cross the placental barrier. Immunophenotypic analyses were performed in 20 healthy HIV-uninfected newborns of HIV-infected mothers (SR), and in 14 healthy newborns of HIV-negative women (UC). The same analyses were performed in 3 groups of older children: SR (n = 41); UC (n = 15); and HIV-infected children (n = 25). Antigen-specific cells were evaluated with ELISpot and fluorimetric analyses; IL-7 serum concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results showed that in SR newborns: (1) the CD4/CD8 ratio was reduced, (2) CD4(+) and CD8(+) naive T-cell percentages were decreased, (3) percentage of activated CD8(+) T cells was increased, and (4) percentages of CD3(+)/4(-)/8(-) (DN) and DN/25(-)/44(+) were augmented. These abnormalities were partially retained in older SR children. CD4(+) and CD8(+) HIV-specific cells were detected in a portion of newborn SRs but not in older SRs. Serum IL-7 was augmented both in newborn and older SRs. Cell-mediated immunity and T-cell maturation are altered even in HIV-uninfected newborns of HIV-infected mothers; these abnormalities persist over time. The biologic significance of these observations and potential subsequent clinical events should be investigated in larger cohorts of seroreverters. (Blood. 2000;96:3866-3871)

Primary Objective: The prevalence of osteoporotic fracture is higher in non-Hispanic Caucasian (NHC) than Mexican-American (MA) women in the USA. The present study examined bone mineral density (BMD) in these two ethnic groups and the association between BMD and body composition., Research Design: Cross-sectional., Subjects: Sixty-two NHC and 54 MA women, aged 60-86 years, with a body mass index (kgm(-2)) of <30., Methods: BMD (gcm(-2)) of the spine (L2-4), hip (femoral neck, trochanter, Ward's triangle) and whole body was determined by dual-energy X-ray absorptiometry (DXA). Bone mineral-free lean mass (LM) and fat mass (FM) and several ratios of body fat distribution were also assessed by DXA., Results: There was no difference in age (NHC, 69.5+/-0.7; MA 69.5+/-0.9 years; mean +/- SEM) or body mass, but MA women were shorter with a higher truncal adiposity (p < 0.001). There was no significant difference in BMD between groups, however, adjusting for height resulted in higher hip and whole body BMD in MA women (p < 0.01). When volumetric bone density was calculated (bone mineral apparent density; BMAD, gcm(-3)), a trend for higher values in MA women was observed at the femoral neck (p = 0.018). LM contributed independently to BMD at the spine and hip in NHC women, with FM also contributing at the femoral neck. In MA women, LM was an independent contributor to lumbar spine and trochanter BMD, and both LM and FM contributed to whole body BMD. However, the effects of LM and FM were removed in both groups when BMD was adjusted for body or bone size, the only exception being at the trochanter in NHC women., Conclusions: These results indicate that MA women have higher bone density at the proximal femur than NHC women, which may partially account for their lower rate of hip fracture. Further, differences in bone density between the two ethnic groups do not appear to be dependent on soft-tissue composition.