A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVES: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). METHODS: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. RESULTS: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05). CONCLUSIONS: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.     

Long distance transport of ragweed pollen as a potential cause of allergy in central Italy.

BACKGROUND: Ambrosia pollen is an important allergen in North America and, as recently discovered, in some European countries. In Italy, the most affected area is the northeast, whereas ragweed has not been reported in the central and southern parts of the country. OBJECTIVE: To identify the source of ragweed pollen detected in Florence and Pistoia in central Italy. METHODS: Ragweed pollen data were collected in Florence and Pistoia for a 6-year period (1999-2004). The relationship between pollen counts and local ground prevalent wind directions was evaluated with analysis of variance and the least significant difference test. Weather conditions were also evaluated on a large-scale circulation pattern by analyzing weather maps and air mass back trajectories. RESULTS: A highly statistically significant relationship between daily prevailing wind direction and pollen count was found in the period under investigation; the ragweed pollen peaks were recorded when winds from northeast in Florence and north-northeast in Pistoia were observed. The synoptic weather situation and the path of back trajectories suggest an area around southern Hungary as a possible source of Ambrosia pollen. Furthermore, the pollen count was above the clinical threshold several times in both Florence and Pistoia. CONCLUSIONS: Several factors indicate that the detection of ragweed pollen in central Italy is due to long distance transport. Taking into consideration the high allergenicity of Ambrosia pollen, the present findings, if confirmed, suggest that the number of sensitized individuals might significantly increase in the near future.     

Failure of primary breast cancer neoangiogenesis to predict pattern of distant metastasis

In the present study, the primary tumor angiogenesis characteristics of 81 stage IV previously untreated breast cancers with synchronous metastasis to different distant sites (10 patients with soft tissue metastases, 31 with bone metastases, and 40 with visceral metastases) were analyzed. The primary intratumor microvessel density was assessed by immunohistochemical assay on paraffin-embedded primary tumor samples, using a monoclonal anti-CD34 antibody. The mean primary intratumor microvessel density (at 400× fields) was 78±39 (SD) microvessels per field. The microvessel density was not significantly related to the main clinical/pathological features of the tumor (age, cytohistological grade, DNA ploidy, diameter, and receptor status). The percentage of tumor cases with high primary intratumor microvessel density (cut-off median value of the series 73±39 microvessels/field) did not significantly differ in patients with bone, soft tissue, or visceral metastatic disease. Aanalysis of clinical outcome showed a significantly shorter time to progression and overall survival for patients with visceral metastases (P<0.001 and P<0.0002 by log-rank, respectively). Presence of visceral metastases was confirmed to be the only independent prognostic factor related to a worse TTP (hazard risk 2.15, 95% confidence interval 1.14–4.03, P<0.02) and overall survival (hazard risk 1.81, 95% confidence interval 0.98–3.35, P<0.06) by multivariate analysis. In conclusion, the assessment of neoangiogenesis of primary breast cancer by CD34 expression does not provide information predictive of different distant sites of metastasis. Received: 15 June 2001 / Accepted: 12 September 2001     

Probiotic lactobacilli: an innovative tool to correct the malabsorption syndrome of vegetarians?

Vegetarians may have subtle nutritional deficiencies which have been related to the occurrence of an unrecognized malabsorption syndrome. The excess phytate content in cereals, nuts, legumes and oilseeds which represent the mainstay of their food intake, seems to play a central role in the pathogenesis of this malabsorption syndrome as an inverse relationship has been shown to link the phytate content of the diet with the intestinal absorption of trace minerals and proteins. We postulate that manipulating the endogenous digestive microflora of subjects on a vegetarian diet through administering probiotic lactic bacteria would represent an innovative tool to counteract the occurrence of the malabsorption syndrome dependent on the high phytate content of their diet. Even though there are no data about the composition of endogenous digestive microflora in subjects on a vegetarian diet, we expect that probiotic lactobacilli can interact with or affect distinct yet interrelated components within the intestinal milieu, such as epithelial cells, enteric flora, and/or mucosal immune cells. This would ultimately translate into the correction of the unregulated mechanisms implicated in the altered intestinal absorption of trace metals and proteins commonly seen in vegetarians. Clinical experience with probiotic therapy of patients with inflammatory bowel disease fully agrees with this view. One additional point of interest is that probiotic lactobacilli, and other species of the endogenous digestive microflora as well, are an important source of the enzyme phytase which catalyses the release of phosphate from phytate and hydrolyses the complexes formed by phytate and metal ions or other cations, rendering them more soluble ultimately improving and facilitating their intestinal absorption. The regular intake of probiotic preparation, may represent a cheap and safe tool in order to convert a diet with a low potential for bioavailability of trace minerals and proteins, such as the vegetarian diet, into a diet with a high bioavailability potential. The benefit of such an approach would not be restricted to vegetarians.     

Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease

Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.     

Moraxella catarrhalis--infected alveolar epithelium induced monocyte recruitment and oxidative burst

The recruitment of monocytes appears to be a crucial factor for inflammatory lung disease. Alveolar epithelial cells contribute to monocyte influx into the lung, but their impact on monocyte inflammatory capacity is not entirely clear. We thus analyzed the modulation of monocyte oxidative burst by A549 and isolated human alveolar epithelial cells. Epithelial infection with Moraxella catarrhalis induced monocyte adhesion, transepithelial migration, and superoxide generation, whereas stimulation with lipopolysaccharide, tumor necrosis factor-alpha, interleukin-1beta, or interferon-gamma induced adhesion or transmigration, but failed to initiate monocyte burst. The effect of microbial challenge was mimicked by phorbol myristate acetate and inhibited by the protein kinase C inhibitor bisindoylmaleimide. Furthermore, evidence for a role of platelet-activating factor-signaling in monocytes is presented. Monocyte burst was neither induced by supernatant nor affected by fixation of A549 cells, excluding the contribution of epithelium-derived soluble factors but emphasizing the mandatory role of intercellular contact. The employment of blocking antibodies, however, denied a role for the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, or CD11b/CD18 and CD49d/CD29. In essence, infection of alveolar epithelial cells with M. catarrhalis might amplify the inflammatory capacity of invading monocytes eliciting their superoxide production. The epithelial response to this microbial challenge thus clearly differed from that to proinflammatory cytokines.     

The dual role of IL-10

Classification of cytokines as pro-versus anti-inflammatory might not apply to the pleiotropic effects of interleukin-10 (IL-10). Several reports suggest that IL-10 enhances the function of natural killer cells, which leads, through pathogen destruction, to increased antigen availability. In addition, by inhibiting the maturation of antigen-presenting cells (APCs), IL-10 preserves their ability for antigen uptake while simultaneously hampering their migration to draining lymph nodes. This review suggests that this "antigen-loading" phase might constitute an important component of the innate immune reaction to a pathogen. Additional proinflammatory stimuli might subsequently lead to maturation of "loaded" APCs that could migrate to draining lymph nodes or recruit and activate adaptive immune effectors locally.     

Incidence of chromosomal imbalances in advanced colorectal carcinomas and their metastases

Comparative genomic hybridization (CGH) was used to screen 54 advanced colon carcinomas. i.e., 24 primary tumors and 30 metastases, for chromosomal alterations. Using a sensitive statistical method for the determination of DNA imbalances and histograms for analysis of the incidence of changes, we identified the DNA over-representation of chromosome 20q as the most common alteration being present in 100% of cases. High incidence deletions were observed on 18q21-18q23 (96%), 4q27-4q28 (96%), 4p14 (87%), 5q21 (81%), 1p21-1p22 (72%), 21q21 (74%), 6q16 (72%), 3p12 (66%), 8p24-8p21 (66%), 9p21 (64%), 11q22 (64%), and 14q13-14q21 (64%). Further frequent over-representation was found on 7q12-7q11.2 (75%), 16p11-16p12 (70%), 19p13 (70%), 9q34 (67%), 19q13 (67%), 13q34 (64%), 13q13 (64%), 17q21 (59%), 22q11 (61%), 8q24 (57%), and 1q21 (57%). Pronounced DNA gains and losses being defined as regions in which the ratio profiles exceeded the values of 1.5 and 0.5, respectively, frequently colocalized with peaks of incidence curve. The use of difference histograms for the comparison of tumor subgroups as well as case-by-case histogram for the analysis of 15 paired tumor samples identified several of the above alterations as relevant for tumor progression and metastasis formation. The study identified additional loci and delineates more precisely those that have been previously reported. For comparative purposes, we have made our primary data (ratio profiles, clinicopathological parameters, histograms) available at the interactive web site http://amba.charite.de/cgh, where the incidence of changes can be determined at individual loci and additional parameters can be applied for the analysis of our CGH results.     

Dissection of seroreactivity against the tryptophan-rich motif of the feline immunodeficiency virus transmembrane glycoprotein

Immunogenicity of the tryptophan-rich motif (TrpM) in the membrane-proximal ectodomain of the transmembrane (TM) glycoprotein of feline immunodeficiency virus (FIV) was investigated. Peptide 59, a peptide containing the TrpM of the TM of FIV, was covalently coupled to Qbeta phage virus-like particles (Qbeta-59) in the attempt to induce potent anti-TrpM B cell responses in cats. All Qbeta-59 immunized cats, but not cats that received a mixture of uncoupled Qbeta and peptide 59, developed antibodies that reacted with a same epitope in extensive binding and binding competition assays. The epitope recognized was composed of three amino acids, two of which are adjacent. However, Qbeta-59-immune sera failed to recognize whole FIV in all binding and neutralization assays performed. Furthermore, no reactivity against the TrpM was detected by screening sera from FIV-infected cats that had reacted with TM peptides, confirming that this epitope does not seem to be serologically functional in the FIV virion. The data suggest that TrpM may not be a suitable target for antiviral vaccine design.