Health in Down syndrome: creating a conceptual model.

BACKGROUND: Down syndrome (DS) has a unique medical and psychological profile that could impact how health is defined on three dimensions: physical, social and mental well-being. METHODS: In 2021, we presented our proposed conceptual model to three expert panels, four focus groups of parents of individuals with DS age 0-21 years and four focus groups of individuals with DS age 13-21 years through videoconferencing technology. Participants gave feedback and discussed the concept of health in DS. RESULTS: Feedback from participants resulted in iterative refinement of our model, retaining the three dimensions of health, and modifying constructs within those dimensions. Experts and parents agreed that individuals with DS have unique health concerns that necessitate the creation and validation of a syndrome-specific health model. We present key themes that we identified and a final conceptual model of health for individuals with DS. CONCLUSION: Health in DS is a multi-dimensional, multi-construct model focused on relevant constructs of causal and effect indicators. This conceptual model can be used in future research to develop a syndrome-specific measure of health status.

Effects of different metabolic states and surgical models on glucose metabolism and secretion of ileal L-cell peptides: results from the HIPER-1 study.

AIM: To compare the impact of four surgical procedures (mini-gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition) vs medical management on gut peptide secretion, ß-cell function and resolution of hyperglycaemia in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A mixed-meal tolerance test was administered 6-24 months after each surgical procedure (mini-gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition; n=30 in each group) and the results were compared with those obtained in matched lean (n=30) and obese (n=30) people with type 2 diabetes undergoing medical management. RESULTS: Participants in the mini-gastric bypass and ileal transposition groups had a greater increase in plasma glucose concentration after the mixed-meal tolerance test than those in the sleeve gastrectomy and transit bipartition groups. Participants in the mini-gastric bypass group exhibited the greatest increase in the incremental area under the curve of plasma glucose concentration above baseline (P<0.0001). Insulin sensitivity was similar across surgical groups, and statistically greater in participants in the surgical groups than in obese participants in the non-surgical group (P<0.0001). ß-cell responsiveness to glucose was greater in participants in the sleeve gastrectomy and transit bipartition groups than in the mini-gastric bypass and ileal transposition groups (P<0.001) despite a smaller incremental increase above baseline in the area under the plasma glucagon-like peptide-1 concentration curve relative to ileal transposition. Postoperative ß-cell function was the strongest predictor of hyperglycaemia resolution. CONCLUSIONS: The present study showed that the level of ß-cell function after bariatric surgery is the strongest predictor of hyperglycaemia resolution. The study also demonstrates a disconnect between postprandial GLP-1 levels and ß-cell function among the studied surgical procedures.

Injury narratives in occupational safety and health prevention in Italy.

BACKGROUND: Storytelling is an effective information source when coupled with technical-scientific evidence. It can promote a structured relationship between evidence-based knowledge and field experience of workplace safety and prevention services (WSPS) inspectors. This is key to identifying the causes of workplace injuries and to set priorities for prevention strategies. AIMS: The main aim was to describe and report how story collection can be used for deriving validated indications for injury prevention. The specific objectives were to report the results of the creation and dissemination on the web of the story collection and the experience of setting up a community of practice (CoP) to develop preventive recommendations. METHODS: WSPS inspectors from local health boards in Piedmont (northwest Italy) were asked to write injury stories. They identified the key elements of their stories and developed a narrative of witness accounts to explore the critical issues identified during the investigation. In sessions with the CoP, the inspectors validated the indications for prevention elaborated in each story to reduce bias and standardize recommendations. RESULTS: Between 2012 and 2017, 60 WSPS inspectors wrote 53 injury stories which were collected and published on the institutional website. Twenty-two stories were selected for discussion during peer review sessions in the CoP and the indications for prevention were transformed as preventive solutions. CONCLUSIONS: Occupational safety and health prevention can benefit from a narrative-based approach that provides a more comprehensive look at health and safety by facilitating knowledge improvement and sharing.

Pharmacogenetic study of long-term response to interferon-ß treatment in multiple sclerosis.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-ß (IFNß) (4-year follow-up). We performed a genome-wide association study in 337 IFNß-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNß-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNß stimulation in HC (P=3.1 × 10-9 and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNß administration (ß=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNß.

Habitat use, but not gene flow, is influenced by human activities in two ecotypes of Egyptian fruit bat (Rousettus aegyptiacus).

Understanding the ecological, behavioural and evolutionary response of organisms to changing environments is of primary importance in a human-altered world. It is crucial to elucidate how human activities alter gene flow and what are the consequences for the genetic structure of a species. We studied two lineages of the Egyptian fruit bat (Rousettus aegyptiacus) throughout the contact zone between mesic and arid Ecozones in the Middle East to evaluate the species' response to the growing proportion of human-altered habitats in the desert. We integrated population genetics, morphometrics and movement ecology to analyse population structure, morphological variation and habitat use from GPS- or radio-tagged individuals from both desert and Mediterranean areas. We classified the spatial distribution and environmental stratification by describing physical-geographical conditions and land cover. We analysed this information to estimate patch occupancy and used an isolation-by-resistance approach to model gene flow patterns. Our results suggest that lineages from desert and Mediterranean habitats, despite their admixture, are isolated by environment and by adaptation supporting their classification as ecotypes. We found a positive effect of human-altered habitats on patch occupancy and habitat use of fruit bats by increasing the availability of roosting and foraging areas. While this commensalism promotes the distribution of fruit bats throughout the Middle East, gene flow between colonies has not been altered by human activities. This discrepancy between habitat use and gene flow patterns may, therefore, be explained by the breeding system of the species and modifications of natal dispersal patterns.

Systemic lupus erythematosus developing immediately after necrotizing fasciitis.

Necrotizing fasciitis (NF) is a medical-surgical emergency characterized by severe bacterial infection that affects the subcutaneous tissue and spreads to the underlying fascia; usually it is caused by penetrating trauma, sometimes by surgical therapy, very rarely by minor insults such as insect bites. Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease involving virtually all the key components of the immune system. Although cases of post-infection autoimmunity were already described, a literature search using Pub Med and Medline revealed that SLE was never reported to occur in patients affected, immediately before, with NF. We observed and herein report, however, a case of a woman showing an insect-bite-induced NF, which was immediately followed by the development of a SLE. In conclusion, this case of postinfection autoimmunity provides early evidence of a patient developing SLE immediately after NF, and suggests that caution in the follow-up of NF is necessary, because NF might favor the development of a severe autoimmunity.

Burden of rare coding variants in an Italian cohort of familial multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. OBJECTIVE: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families. METHODS: We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. RESULTS: We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10-4 and 3 × 10-4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. CONCLUSION: Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.

Aromatase inhibitor-induced skin adverse reactions: exemestane-related cutaneous vasculitis.

BACKGROUND: Three aromatase inhibitors, namely anastrozole, letrozole and exemestane, which reduce circulating oestrogen, are used to treat breast cancer patients; the therapeutic use of such aromatase inhibitors is quickly increasing. OBJECTIVE: We intended (i) to review aromatase inhibitor-induced cutaneous adverse effects and (ii) to describe a recently observed case of cutaneous vasculitis triggered by exemestane. PATIENTS/METHODS: The so-far reported literature cases of aromatase inhibitor-induced cutaneous adverse effects were analysed retrospectively. Especially, the clinical case of exemestane-induced cutaneous vasculitis herein reported is unique, because such an observation has not yet been published in the literature. RESULTS: Merely 12 cases of cutaneous adverse reactions induced by aromatase inhibitors, namely erythema nodosum (6), subacute cutaneous lupus erythematosus (1), cutaneous rashes (2), vasculitis (3, including the one described in this study), are reported in the literature. In fact, in the present case, cutaneous vasculitis was strictly related to exemestane. CONCLUSION: As aromatase inhibitors (e.g. exemestane) are increasingly incorporated into the treatment strategy of breast cancer patients, it is important to recognize possible cutaneous adverse effects. Specifically, with regard to cutaneous vasculitis, some patients might progress to severe vasculitis manifestations if the offending drug (e.g. exemestane) is not quickly stopped.

Transcriptomic Analysis of Peripheral Monocytes upon Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients.

Fingolimod (FTY), a second-line oral drug approved for relapsing remitting Multiple Sclerosis (RRMS) acts in preventing lymphocyte migration outside lymph nodes; moreover, several lines of evidence suggest that it also inhibits myeloid cell activation. In this study, we investigated the transcriptional changes induced by FTY in monocytes in order to better elucidate its mechanism of action. CD14+ monocytes were collected from 24 RRMS patients sampled at baseline and after 6 months of treatment and RNA profiles were obtained through next-generation sequencing. We conducted pathway and sub-paths analysis, followed by centrality analysis of cell-specific interactomes on differentially expressed genes (DEGs). We investigated also the predictive role of baseline monocyte transcription profile in influencing the response to FTY therapy. We observed a marked down-regulation effect (60 down-regulated vs. 0 up-regulated genes). Most of the down-regulated DEGs resulted related with monocyte activation and migration like IL7R, CCR7 and the Wnt signaling mediators LEF1 and TCF7. The involvement of Wnt signaling was also confirmed by subpaths analyses. Furthermore, pathway and network analyses showed an involvement of processes related to immune function and cell migration. Baseline transcriptional profile of the HLA class II gene HLA-DQA1 and HLA-DPA1 were associated with evidence of disease activity after 2 years of treatment. Our data support the evidence that FTY induces major transcriptional changes in monocytes, mainly regarding genes involved in cell trafficking and immune cell activation. The baseline transcriptional levels of genes associated with antigen presenting function were associated with disease activity after 2 years of FTY treatment.

Identification of differential DNA methylation associated with multiple sclerosis: A family-based study.

Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to influence MS risk. Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®). Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13. These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.

Human amygdala reactivity is diminished by the ß-noradrenergic antagonist propranolol.

BACKGROUND: Animal models of anxiety disorders emphasize the crucial role of locus ceruleus-noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a ß-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a ß-noradrenergic modulation of BLA activity in humans is missing. METHOD: We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a ß-noradrenergic receptor blockade with propranolol would inactivate the BLA. RESULTS: Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA. CONCLUSIONS: Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of ß-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via ß-noradrenergic receptors.

[Integrated use of data bases to map manufacturing processes involving exposure to carcinogens in the Piedmont Region: the example of formaldehyde]. / Uso integrato di banche dati per la mappatura di lavorazioni con esposizione a cancerogeni nella Regione Piemonte: l'esempio della formaldeide.

BACKGROUND: Exposure to carcinogens is still widespread in working environments. For the purpose of defining priority of interventions, it is necessary to estimate the number and the geographic distribution of workers potentially exposed to carcinogens. It could therefore be useful to test the use of tools and information sources already available in order to map the distribution of exposure to carcinogens. Formaldehyde is suggested as an example of an occupational carcinogen in this study. OBJECTIVES: The study aimed at verifying and investigating the potential of 3 integrated databases: MATline, CAREX, and company databases resulting from occupational accident and disease claims (INAIL), in order to estimate the number of workers exposed to formaldehyde and map their distribution in the Piedmont Region. METHODS: The list of manufacturing processes involving exposure to formaldehyde was sorted by MIATline; for each process the number of firms and employees were obtained from the INAIL archives. By applying the prevalence of exposed workers obtained with CAREX, an estimate of exposure for each process was determined. A map of the distribution of employees associated with a specific process was produced using ArcView GIS software. RESULTS: It was estimated that more than 13,000 employees are exposed to formaldehyde in the Piedmont Region. The manufacture of furniture was identified as the process with the highest number of workers exposed to formaldehyde (3,130),followed by metal workers (2,301 exposed) and synthetic resin processing (1,391 exposed). CONCLUSION: The results obtained from the integrated use of databases provide a basis for defining priority of preventive interventions required in the industrial processes involving exposure to carcinogens in the Piedmont Region.

PDGF induction of alpha 2 integrin gene expression is mediated by protein kinase C-zeta.

Platelet-derived growth factor (PDGF) stimulates fibroblasts to move over collagen and contract three-dimensional collagen gels, processes important in wound repair and fibrocontractive diseases. These processes depend on alpha 2 beta 1 integrin ligation of collagen and PDGF induces the expression of this integrin. Several lines of evidence presented here suggest that PKC-zeta plays a role in alpha 2 integrin gene expression. The induction was blocked by chemical inhibitors for protein tyrosine kinases (PTK), genistein, and protein kinase C (PKC), chelerythrine, and bisindolylmaleimide GF 109203X. Cells depleted of phorbol 12-myristate 13-acetate (PMA)-inducible PKCs by chronic treatment with PMA still demonstrated an alpha 2 response to PDGF indicating that a non-PMA-sensitive PKC isoform was required. PDGF induced kinase activity in PKC-zeta immunoprecipitates. Antisense oligonucleotides complementary to 5' end of PKC-zeta mRNA sequences blocked the PDGF-induced increase of alpha 2 mRNA levels up to 70%, indicating PKC-zeta, a non-PMA-sensitive PKC isoform, is a component of the PDGF stimulatory pathway for alpha 2 mRNA synthesis. A 961-base pair (bp) upstream region of alpha 2 gene/CAT construct transfected into human dermal fibroblasts was positively regulated by PDGF as judged by CAT enzymatic levels. Both PTK and PKC inhibitors blocked PDGF-stimulation of the alpha 2 promoter fragment/CAT construct, indicating that the phosphorylation requirement occurred at alpha 2 promoter-directed transcription level. Therefore, we propose that PDGF-stimulatory pathway of alpha 2 integrin gene expression involves multiple cellular protein kinases, one of which is PKC-zeta.

A three-dimensional collagen lattice activates NF-kappaB in human fibroblasts: role in integrin alpha2 gene expression and tissue remodeling.

Normal adult human dermal fibroblasts grown in a three-dimensional collagen lattice increase mRNA level of collagen receptor integrin subunit alpha2 (Xu, J., and R.A.F. Clark. 1996. J. Cell Biol. 132:239- 249.) and DNA binding activity of a nuclear transcription factor, NF-kappaB (Xu, J., and R.A.F. Clark. 1997. J. Cell Biol. 136:473-483.). Here we present evidence that the collagen lattice induced the nuclear translocation of p50, one member of NF-kappaB family, and the degradation of an NF-kappaB inhibitor protein, IkappaB-alpha. The inhibition of NF-kappaB activity by SN50, a peptide inhibitor targeted at nuclear translocation of NF-kappaB, significantly reduced the induction of integrin alpha2 mRNA and protein by the collagen lattice. A region located between -549 and -351 bp in the promoter of integrin alpha2 gene conferred the inducibility by three-dimensional collagen lattice. The presence of either SN50 or IkappaB-alpha32, 36, a stable mutant of IkappaB-alpha, abrogated this inducibility, indicating that the activation of integrin alpha2 gene expression was possibly mediated by NF-kappaB through this region. Although there were three DNA-protein binding complexes forming in this region that are sensitive to the inhibition of NF-kappaB nuclear translocation, NF-kappaB was not directly present in the binding complexes. Therefore, an indirect regulatory mechanism by NF-kappaB in integrin alpha2 gene expression induced by three-dimensional collagen lattice is suggested. The involvement of NF-kappaB in reorganization and contraction of three-dimensional collagen lattice, a process that requires the presence of abundant integrin alpha2beta1, was also examined. The inhibition of NF-kappaB activity by SN50 greatly blocked the contraction, suggesting its critical role in not only the induction of integrin alpha2 gene expression by three-dimensional collagen lattice, but also alpha2beta1-mediated tissue-remodeling process.

The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen.

We have purified the platelet membrane glycoprotein Ia-IIa complex by detergent solubilization and sequential affinity chromatography on Concanavalin A-Sepharose and collagen-Sepharose. The complex, which is identical to the VLA-2 complex of lymphocytes and other cells and contains subunits of 160 and 130 kD on SDS-PAGE, was labeled with 125I and incorporated into phosphatidyl choline liposomes. The liposomes, like intact platelets, adhered to collagenous substrates in an Mg++-dependent manner with a K'a(Mg++) of 3.5 mM. Little adhesion of the liposomes to collagen occurred when Mg++ was replaced by Ca++ or EDTA. Calcium ions inhibited the Mg++-dependent adhesion with a K'i(Ca++) of 5.5 mM. Liposomes containing the Ia-IIa complex adhered to substrates composed of types I, II, III, and IV collagen, but did not effectively adhere to substrates composed of type V collagen or gelatin. Adhesion to collagen was specific. The liposomes did not adhere to fibronectin, vitronectin, laminin, thrombospondin, fibrinogen, or von Willebrand factor substrates. The monoclonal antibody P1H5, which specifically immunoprecipitated the Ia-IIa complex, also specifically inhibited the Mg++-dependent adhesion of both platelets and Ia-IIa-containing liposomes to collagen substrates. These findings provide additional evidence that the platelet membrane Ia-IIa complex is the mediator of Mg++-dependent platelet adhesion to collagen and suggest that the VLA-2 complex may also function as an Mg++-dependent collagen receptor in other cells.

Mapping of epitopes for monoclonal antibodies against human platelet thrombospondin with electron microscopy and high sensitivity amino acid sequencing.

A panel of monoclonal antibodies (Mab's) has been raised against human platelet thrombospondin (TSP). One Mab, designated A2.5, inhibits the hemagglutinating activity of TSP and immunoprecipitates the NH2 terminal 25 kD heparin binding domain of TSP (Dixit, V.M., D. M. Haverstick, K. M. O'Rourke, S. W. Hennessy, G. A. Grant, S. A. Santoro, and W. A. Frazier, 1985, Biochemistry, in press). Another Mab, C6.7, blocks the thrombin-stimulated aggregation of live platelets and immunoprecipitates an 18-kD fragment distinct from the heparin binding domain (Dixit, V. M., D. M. Haverstick, K. M. O'Rourke, S. W. Hennessy, G. A. Grant, S. A. Santoro, and W. A. Frazier, 1985, Proc. Natl. Acad. Sci. 82: 3472-3476). To determine the relative locations of the epitopes for these Mabs in the three-dimensional structure of TSP, we have examined TSP-Mab complexes by electron microscopy of rotary-shadowed proteins. The TSP molecule is composed of three 180-kD subunits, each of which consists of a small globular domain (approximately 8 nm diam) and a larger globular domain (approximately 16 nm diam) connected by a thin, flexible strand. The subunit interaction site is on the thin connecting strands, nearer the small globular domains. Mab A2.5 binds to the cluster of three small domains, indicating that this region contains the heparin binding domain and thus represents the NH2 termini of the TSP peptide chains. Mab C6.7 binds to the large globular domains on the side opposite the point at which the connecting strand enters the domain, essentially the maximum possible distance from the A2.5 epitope. Using high sensitivity automated NH2 terminal sequencing of TSP chymotryptic peptides we have ordered these fragments within the TSP peptide chain and have confirmed that the epitope for C6.7 in fact lies near the extreme COOH terminus of the peptide chain. In combination with other data, we have been able to construct a map of the linear order of the identified domains of TSP that indicates that to a large extent, the domains are arranged co-linearly with the peptide chain.

Cytoplasmic beta-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis?

BACKGROUND: An excess of intracellular beta-catenin protein is triggered by various genetic alterations in melanoma cell lines, and has been suggested to play a role in melanoma tumorigenesis. OBJECTIVES: To investigate the role played in vivo by beta-catenin in melanoma tumorigenesis, we compared the cytoplasmic detection of beta-catenin in benign melanocytic cells vs. malignant melanoma cells presumably generated from these benign melanocytic cells. For this purpose, melanocytic naevi occurring in association with melanoma, which were suggested to be melanoma precursors, were compared with their associated melanoma for beta-catenin cytoplasmic immunoreactivity. METHODS: Fifty-seven consecutive cases of primary cutaneous melanoma were considered, and 15 of them were found to be associated with a melanocytic naevus portion. The naevus portion showed features of acquired melanocytic naevus (total 12 cases: five dysplastic, seven intradermal) or congenital growth pattern naevus (total three cases: one superficial, two deep). All specimens were immunohistochemically investigated for beta-catenin. RESULTS: Virtually all primary cutaneous melanomas, including those associated with a naevus portion, showed cytoplasmic beta-catenin positivity. However, the intradermal naevus portion was consistently cytoplasmic beta-catenin negative, while both the dysplastic and the congenital naevus portions were cytoplasmic beta-catenin positive. CONCLUSIONS: Beta-catenin excess may play a role in melanoma tumorigenesis, because beta-catenin cytoplasmic reactivity was found in primary cutaneous melanoma but not in its associated intradermal naevus precursor. As, however, beta-catenin cytoplasmic reactivity was detected not only in primary cutaneous melanoma but also in its associated dysplastic/congenital naevus precursors, beta-catenin stabilization alone is not sufficient to play a decisive role for melanoma onset.

Refractory Takayasu arteritis successfully treated with infliximab.

Takayasu arteritis (TA) is a chronic inflammatory disease of large arteries which progressively develop stenosis, occlusion or aneurismal degeneration. Proinflammatory cytokines and, among these, tumor necrosis factor-alpha (TNF-alpha) are increased and play a pathogenetic role in the development of disease. Conventional therapy often fails to determine clinical remission and, in these cases, pathogenetic strategies with anti-TNF-alpha drugs have been proposed. Infliximab is a human-murine chimeric monoclonal antibody that specifically binds to and neutralizes soluble TNF-alpha. It is an effective treatment for rheumatoid arthritis, spondyloarthritis, Crohn's disease and ulcerative colitis and it has been recently proposed for the treatment of TA in patients refractory to conventional therapy. Here we report the case of a patient affected by Takayasu arteritis unresponsive to conventional therapy who was then treated with infliximab and obtained a clinical remission of the disease.

Wood mouse body size measurements data in a Spanish protected area over two periods spanning thirty years.

We present data of morphometric measurements of a wood mouse Apodemus sylvaticus population collected in the Doñana National Park (SW Spain) in the periods between 1978-81 and 2006-07. These data have been extrapolated from specimens deposited in the Doñana Biological Station Collection. The data in this article support the information provided in the research article "Marked reduction in body size of a wood mouse population in less than 30 years" [1].

Collagen-mediated platelet aggregation. Evidence for multivalent interactions of intermediate specificity between collagen and platelets.

We have shown previously that periodate oxidation of collagen carbohydrate does not affect its ability to aggregate platelets. We now describe an additional characterization of periodate-modified collagen which demonstrates that collagen devoid of intact carbohydrate is fully capable of fibril formation, and we confirm its capacity to initiate platelet aggregation. Furthermore, we demonstrate that the platelet aggregating abilities of Types I, II, and III fibrillar collagen are quite similar despite differences in carbohydrate content and amino acid sequence. We also demonstrate that monomeric, pepsin-solubilized Type I human collagen is ineffective inhibiting aggregation by performed fibrils derived from the same molecule, thus establishing that the affinity of platelets for collagen depends upon prior polymerization of collagen. We interpret these and other findings to demonstrate that the hydroxylysyl glycoside regions of collagen are not highly specific sites involved in platelet-collagen interactions leading to "physiological" aggregation, and that the possibility must be considered that multiple interactions involving collagen sites of comparatively low structural specificity may be the initiating events in release of platelet ADP and the ensuing aggregation.