Mortality study of asbestos cement workers

The present study describes cause-specific mortality of asbestos cement workers in the Emilia Romagna region of Italy. The cohort included workers in ten factories, most of which started operating between 1955 and 1965. Asbestos, mainly chrysotile, constituted 10%–20% of the dry component of the mixture. Crocidolite range between 5% and 50% of total asbestos. Asbestos concentrations up to 44 ff/cc were reported prior to 1975, while in recent years they have usually been below 0–1 ff/cc. The cohort included 3341 workers who had at some time been employed in the ten factories under study. Their mortality experience was compared with that of the population resident in Emilia Romagna. Vital status was ascertained at 1989. Seventy-three subjects were lost to followup (2.2%). Mortality from all causes and from all types of cancer was increased in the cohort. Malignant neoplasms of the respiratory tract showed a significant increase (SMR: 134; 90% confidence interval: 101–175; 40 observed) due to lung cancer (SMR: 124; 90% confidence interval: 91–166; 33 observed) and neoplasms of the pleura, mediastinum, and other parts of the respiratory tract (SMR: 602; 90% confidence interval 237–1267; 5 observed). The discrepancy between observed and expected mortality mainly concerned subjects with at least 20 years of employment in the factories. Five more cases of histologically confirmed mesothelioma occurred after the end of follow-up.     

Pulmonary metastases from epithelial tumours: late results of surgical treatment.

OBJECTIVE: Development of distant metastases is one of the primary characteristics of malignant tumours. During the last decades, lung metastasectomy has been progressively accepted as a therapeutic option in oncology patients. The present paper aims to evaluate the long-term results and factors influencing prognosis in patients submitted to lung resection for metastases from extrapulmonary epithelial tumours. METHODS: We retrospectively analysed data of 202 patients undergoing 207 procedures of lung metastasectomy between January 1980 and December 2003. Factors that may influence long-term prognosis such as completeness of resection, histology of the tumour, disease-free interval, number of resected lesions, involvement of hilar or mediastinal lymph nodes, systemic treatments were investigated. RESULTS: Complete resection was carried out in 169 patients (83.7%). The more frequent lung resection was sublobar in 67.6% of cases, but rarely in selected patients bilobectomy or pneumonectomy has been carried out too. Perioperative morbidity and mortality were 7.7% and 0.9%. Mean disease-free interval was 49+/-48 months. Mean follow-up was 33+/-31 months, 5-year and 10-year survival rates for completely resected patients were 43% and 17%, respectively. By univariate and multivariate analyses, completeness of resection, disease-free interval of 36 months or more, and single resected metastasis were found to be significant prognostic factors. CONCLUSIONS: Resection of epithelial lung metastases allows an acceptable prognostic result in appropriately selected patients with very low perioperative morbidity and mortality. Factors such as high disease-free interval, single metastasis and completeness of resection are demonstrated and confirmed to be significantly associated with long-term survival.     

Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians [see comments]

The contribution of the immune system to healthy aging and longevity is still an open question. For this reason, several immune parameters (T, B, and natural killer [NK] cell subsets; non-major histocompatibility complex [MHC]-restricted cytotoxic activities, ie, natural and redirected killing [RDK] activities) were studied in a total of 138 healthy subjects of different ages, from 4 to 106 years of age, including 26 centenarians. The major age-related modifications were the following: (1) a decrease in the absolute number of T lymphocytes (CD3+), involving both CD4+ and CD8+ subsets, accompanied by a marked concomitant increase in the number of activated T cells (CD3+, HLA- DR+); (2) a marked decrease in the number of B lymphocytes (CD19+); and (3) an increase in the number of cells with markers of NK activity and of T lymphocytes able to mediate non-MHC-restricted cytotoxicity. These modifications linearly progressed with age and centenarians followed the trend, suggesting that their immune system did not escape the aging process. However, other immunohematologic parameters (number of red blood cells, platelets, and leukocytes) and important immune functions, such as cytotoxic activities (NK and RDK cell activities), were well preserved throughout life until the last decades of life. Unexpectedly, in apparently healthy middle-aged subjects, a decrease of cytotoxic activities was observed in comparison with those of both young controls and centenarians. In conclusions, our data suggest that in centenarians some immune responses are kept at a high level of efficiency, likely contributing to their successful aging. However, this selected group of people does not escape the aging process, as shown by the progressive derangement of a variety of immune parameters.     

Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity

In a recent paper, we showed that the number of endoneurial microvessels per square millimeter and the average luminal area and size distribution of these microvessels are not significantly different in sural nerves of patients with diabetes mellitus as compared to control subjects. Mural area, especially the component due to basement membrane reduplication and cellular debris, was unequivocally increased in diabetes mellitus. Because these latter changes are associated with a decrease in periendothelial cell area, we hypothesized that cellular degeneration, especially of pericytes, may account for basement membrane reduplication and increased frequency of cellular debris. In the present study, we showed that endoneurial microvessels undergo a statistically significant increase in basement membrane area, mural area, and frequency of cellular debris in diabetics without polyneuropathy and an even greater increase in diabetics with polyneuropathy. We also found that duration of diabetes mellitus was significantly associated with area occupied by reduplicated basement membrane and cellular debris, but not with mural and periendothelial area. None of the examined measurements was associated with age. Since the microvessel abnormalities we describe are already present before the development of polyneuropathy and increase with severity of polyneuropathy, it is likely that they reflect functional derangements of pericytes and microvessel function which precede and might be implicated in fiber degeneration.     

The natural alliance between type I interferon and dendritic cells and its role in linking innate and adaptive immunity.

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) and thus play a pivotal role in induction of the immune response. Recent studies in both human and mouse models have shown that type I IFN, cytokines originally characterized for their antiviral activity and exerting multiple biologic effects, efficiently promote the differentiation and activation of DCs. These observations, together with the findings that DCs can express biologically relevant levels of type I interferon (IFN) and, in particular, that high amounts of these cytokines are released by specialized DC precursors (i.e., plasmacytoid DCs) in response to viral infections, strongly suggest the existence of a natural alliance between type I IFN and DCs, which is instrumental in ensuring an efficient immune response to both infectious agents and tumors. Further recent knowledge on the interactions between type I IFN and DCs emphasizes the importance of these cytokines in linking innate and adaptive immunity and may lead to new perspectives in their use as vaccine adjuvants as well as in strategies for the development of DC-based vaccines.     

Expression and functional activity of CXCR-4 and CCR-5 chemokine receptors in human thymocytes

In this paper we addressed the expression of the HIV co-receptors CXCR-4 and CCR-5 in human thymocytes by phenotypic, molecular and functional approaches. Cytofluorimetric analysis disclosed that CXCR-4 was constitutively expressed by freshly isolated thymocytes (~10 000 molecules/cell in about 30% of thymocytes); the receptor was endowed with functional activity, as it mediated polarization, migration and intracellular Ca2+ increase in response to its ligand, SDF-1. On the contrary, CCR-5 expression in freshly isolated thymocytes was significantly lower (<4000 molecules/cell in less than 5% of the cells), and no functional response to CCR-5 agonists could be documented. Northern blot analysis of freshly isolated thymocytes showed high CXCR-4 mRNA levels, whereas the message for CCR-5 was barely detectable. On the other hand, a modest increase in the expression of CCR-5 was associated with in vitro thymocyte stimulation, and CCR-5 density at the cell surface attained CXCR-4 figures in most cases. None the less, no functional response to CCR-5 agonists could be documented in in vitro stimulated thymocytes. In vitro infection of thymocytes by CAT-expressing recombinant HIV bearing the envelope glycoproteins from different isolates showed that T-tropic strains, which use CXCR-4 as a co-receptor, were more efficient in infecting thymocytes than M-tropic strains, which preferentially use CCR-5. Altogether, these data indicate that expression of the major co-receptors involved in infection by M-tropic HIV strains is very poor in human thymocytes, and would suggest that thymocyte infection by M-tropic HIV strains may be a rare event in vivo.     

Autosomal dominant Brody disease cosegregates with a chromosomal (2;7)(p11.2;p12.1) translocation in an Italian family

Brody disease is a rare muscle disorder characterized by exercise-induced impairment in muscle relaxation, due to a markedly reduced influx of calcium ions in the sarcoplasmic reticulum. A subset of autosomal recessive families harbour mutations in the ATP2A1 gene, encoding the fast-twitch skeletal muscle sarcoplasmic reticulum Ca(2+) ATPase (SERCA1). Rare autosomal dominant families have been described, in which ATP2A1 was excluded as the causative gene, further supporting genetic heterogeneity. We report four individuals from a three-generation Italian family with a clinical phenotype of Brody disease, in which linkage analysis excluded ATP2A1 as the responsible gene. The disease cosegregates in an autosomal dominant fashion with an apparently balanced constitutional chromosome translocation (2;7)(p11.2;p12.1), suggesting a causal relationship between the rearrangement and the phenotype. FISH analysis using YAC and PAC clones as probes refined the breakpoint regions to genomic segments of about 164 and 120 kb, respectively, providing a possible clue to pinpoint the location of a novel gene responsible for this rare muscle disorder.     

Idiopathic CD4+ lymphocytopenia may be due to decreased bone marrow clonogenic capability

BACKGROUND: Idiopathic CD4+ lymphocytopenia is defined by a stable decrease of CD4+ T cells in the absence of any known cause of immune deficiency. The mechanisms responsible for the immunological impairment are still unknown, but a regenerative failure of hematopoietic stem/progenitor cells has been hypothesized. METHODS: We evaluated in the bone marrow (BM) of 5 patients with idiopathic CD4+ lymphocytopenia the phenotype of BM progenitor cells, their differentiation capacity with colony-forming cells and long-term culture-initiating cell assays, in parallel with the spontaneous IL-7 production in the patient sera. RESULTS: Compared with controls, a regenerative failure of hematopoietic stem cells has been observed, both in 'committed' and in 'uncommitted' progenitor cells, despite high IL-7 serum levels. The percentage of phenotypically primitive CD34+CD38-DR+ cells (this includes the lymphoid precursor cells) was decreased, suggesting an involvement of the more primitive BM compartment in the de novo T cell generation. CONCLUSIONS: Despite the low number of patients, due to the low incidence of the disease, the decrease of primitive precursors sustains the possibility that diminished stem cell precursors might contribute to the development of CD4+ T cell depletion.     

Analysis of the immune response induced by a single xenoantigen in vivo

Transgenic mice expressing human major histocompatibility complex (MHC) class II molecules would provide a valuable model system for studying murine anti-human MHC immune response. We have previously shown that skin from HLA-DR1 transgenic mice was rejected by control littermates and spleen cells from rejecting mice were able to proliferate to donor cells. The aim of this paper is to analyze the mechanism of recognition of this xenoantigen and the possible involvement of antibody response in anti-HLA-DR1 immune response. Control littermates were immunized with spleen cells from HLA-DR1 transgenic (TG) mice; at indicated times, xenoantigen-specific proliferation and IFNgamma production was assessed using APC obtained from HLA-DR1 TG mice. Mixed direct-indirect pathway of xenoantigen recognition was suggested by the following findings: i)T cell response to HLA-DR1 was inhibited adding in culture monoclonal antibodies directed either to donor (HLA-DR) or to recipient MHC (I-A); ii) APC from control mice pulsed with purified DR1 molecules were able to induce proliferation by FVB/N mice immunized with transgenic spleen cells. HLA-DR1 recognition permits DR peptide-specific T cell response by lymphocytes of control littermates immunized with the xenoantigen. In addition, we detected xenoreactive IgM and IgG2 antibodies. Our data suggest that HLA-DR1 xenoantigen may be recognized through direct or indirect pathway and provide additional information on mouse anti-human HLA immune response.