Thromboembolism and breast cancer: the hidden risk for patient and physician.
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Aged↗
Biomedical subjects
L Miele
Publications and source records attributed to L Miele.
Anticholinergic syndrome due to 'Devil's herb': when risks come from the ancient time.
We describe a case of Mandragora autumnalis poisoning which occurred in a 72-year-old female patient who had eaten the venenous M. Autumnalis, picked near her home, mistaking it for the edible Borago Officinalis. M. Autumnalis is a solanaceous plant, common in the Sicilian countryside, which contains a variable concentration of solanum alkaloids, causing gastrointestinal irritation, and tropane alkaloids, with anticholinergic properties. Unluckily, M. Autumnalis is often mistaken for the edible B. Officinalis, likewise widespread in Sicilian countryside. The diagnosis of Mandragora poisoning was made on the basis of clinical symptoms and signs of anticholinergic syndrome associated with a history of vegetable meal of uncontrolled origin, moreover analysing the vegetable obtained from gastric lavage. Decontamination and symptomatic treatment were useful in our patient to control acute poisoning.
Cholinergic Antagonists↗
NOTCH signaling as a novel cancer therapeutic target.
NOTCH-ligand interaction is a highly conserved mechanism that regulates specific cell fate decision during development. In addition to its functions in developmental and cell maturation processes, studies indicate that NOTCH activation plays a role in the onset and progression of many human malignancies. The prevailing new strategy for rationally targeted cancer treatment is aimed at the development of target-selective "smart" drugs on the basis of characterized mechanisms of action. The connection between NOTCH signaling and tumorigenesis suggests that NOTCH may be such a target candidate. Gamma-secretase is a large membrane-integral multisubunit protease complex, which is essential for NOTCH receptor activation. Inhibitors of this enzyme are being developed for Alzheimer's disease, due to its role in cleaving beta-amyloid precursor in the brain. Recently, Gamma-secretase inhibitors (GSIs), as well as various biopharmaceutical or genetic NOTCH signaling inhibitors have been suggested as potential novel cancer therapeutic strategies. This review summarizes the evidence linking NOTCH signaling to several types of cancer, as well as the possible therapeutic indications of NOTCH inhibitors and the challenges facing their clinical development.
Amyloid Precursor Protein Secretases↗
Anisakis infestation: a case of acute abdomen mimicking Crohn's disease and eosinophilic gastroenteritis.
Anisakiasis is a rare parasitic disease transmitted to humans by the ingestion of raw fish, which can initially present with acute abdomen. We report the case of a man, a habitual consumer of raw fish, who underwent surgery for acute abdomen, initially attributed to Crohn's disease and then later interpreted as eosinophilic enteritis. Only the subsequent careful histological examination of the surgical specimen, revealing full thickness eosinophilic infiltrate, generally typical of infestation, led to the detection of Anisakis simplex larva. In cases of acute abdomen, in the presence of a positive history of raw fish ingestion, it is therefore reasonable to consider the possibility of anisakiasis.
Abdomen, Acute↗
Fulminant liver failure caused by cyproterone.
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Aged↗
Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre.
BACKGROUND: Several prognostic models have been developed to stage hepatocellular carcinoma (HCC) but there is no general consensus on which is the most reliable. We compared three prognostic indices (Okuda, CLIP, and BCLC scoring systems) in a large series of cirrhotic patients with HCC undergoing non-surgical treatment in terms of their ability to classify patients into different risk groups METHODS: We retrospectively studied 268 Italian patients with HCC. A total of 146 patients were treated with ablation, 132 with percutaneous ethanol injection, and 14 with radiofrequency ablation; 103 underwent transcatheter arterial chemoembolisation and 19 had supportive care alone. Factors determining survival were analysed by univariate and multivariate analysis using the Kaplan-Meier method and Cox proportional hazard regression models. Okuda, CLIP, and BCLC scores evaluated before treatment were applied. RESULTS: Median survival was 25.7 months. In a multivariate analysis, portal vein thrombosis, alpha fetoprotein, total bilirubin, and tumour size were significant predictors of survival. Okuda, CLIP, and BCLC scores were all able to predict survival (p<0.001). They identified two, four, and six risk groups, respectively, with a median survival ranging from 27 to 19 months for Okuda, 30 to 5 months for CLIP, and 43 to 7 months for BCLC. CONCLUSIONS: Both CLIP and BCLC scores were more effective than the Okuda score in stratifying patients into different risk groups with early-intermediate HCC. However, the BCLC scoring system gave a better prediction of prognosis in patients with disease diagnosis at a very early stage.
Adult↗
High efficacy of 1-week doxycycline- and amoxicillin-based quadruple regimen in a culture-guided, third-line treatment approach for Helicobacter pylori infection.
BACKGROUND: Helicobacter pylori infection may persist after both first- and second-line current treatments. AIM: To assess the efficacy of a third-line, culture-guided treatment approach for the eradication of H. pylori. METHODS: Patterns of resistance were analysed in H. pylori isolates from 94 consecutive patients in whom H. pylori infection had persisted after two eradication attempts. Using the epsilometer test, susceptibility analysis was performed for amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin. Patients were then treated with a culture-guided, third-line regimen: 89 patients with a 1-week quadruple regimen including omeprazole, bismuth, doxycycline and amoxicillin, and five patients with a 1-week triple regimen containing omeprazole, amoxicillin and levofloxacin or clarithromycin. RESULTS: Ninety-four subjects (100%) were resistant to metronidazole, 89 (95%) to clarithromycin, 29 (31%) to levofloxacin and five (5%) to tetracycline. No resistance to amoxicillin was found in any patient. Overall, H. pylori eradication was obtained in 90% of subjects. The quadruple regimen was effective in 81 patients (92% by per protocol and 91% by intention-to-treat analysis). Four patients (80%, both per protocol and intention-to-treat analysis) were H. pylori-negative after the triple regimen. CONCLUSIONS: A culture-guided, third-line therapeutic approach is effective for the eradication of H. pylori. Furthermore, the 1-week doxycycline- and amoxicillin-based quadruple regimen is a good third-line 'rescue' treatment option.
Amoxicillin↗
New developments about the association of SV40 with human mesothelioma.
Simian virus 40 (SV40) has been detected in human tumors in over 40 different laboratories. Many of these reports linked SV40 to human mesotheliomas. The Vaccine Safety Committee of the Institute of Medicine (IOM), National Academy of Sciences, USA, recently reviewed the evidence associating polio vaccines and/or SV40 with human tumors. The IOM conclusions about polio vaccines and human cancer were: (1) 'the evidence is inadequate to accept or reject a causal relation between SV40-containing polio vaccines and cancer' because the 'epidemiological studies are sufficiently flawed'; (2) 'the biological evidence is of moderate strength that SV40 exposure from the polio vaccines is related to SV40 infection in humans'. The epidemiological studies were considered flawed because it was not possible to distinguish reliably among exposed and nonexposed cohorts. Concerning SV40, the IOM concluded that (1) 'the evidence is strong that SV40 is a transforming virus; (2) the evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions' (IOM, 2002). Similar conclusions were reached at an International consensus meeting on SV40 and human tumors held at the University of Chicago in 2001. G Klein and C Croce, who chaired the final panel that reviewed all the published evidence linking SV40 to human tumors, stated that 'the presence of SV40 in human tumors has been convincingly demonstrated' (Klein et al., 2002). In addition, a workshop organized by the Biological Carcinogenesis Branch of the National Cancer Institute, Bethesda, MD, chaired by J Pagano, has reached similar conclusions (Wong et al., 2002). Therefore, three independent scientific panels have all agreed that there is compelling evidence that SV40 is present in some human cancers and that SV40 could contribute to the pathogenesis of some of them. It should be noted that the presence of SV40 in mesothelioma and other human tumor types has been challenged by a research team that has consistently reported negative findings (Strickler et al., 2001). However, a member of this research team has recently acknowledged - in sworn testimony -sensitivity problems and possible irregularities that raise concerns about these negative reports (MacLachlan, 2002). These revelations, together with the conclusions of the three independent panels mentioned above, appear to bring to an end the apparent controversy about the presence of SV40 in human mesotheliomas and brain tumors.
Humans↗
Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma.
Establishing an effective epidermal barrier requires a series of coordinated molecular events involving keratinocytes (KCs) within a stratified epithelium. Epidermal maturation depends on convergence of pathways involving components of NF-kappaB and peroxisome proliferator activated receptor (PPAR) signaling systems that promote terminal differentiation and production of a stratum corneum. The Notch-1 receptor and its ligand Delta-1 have been proposed by others to participate in early events in KC differentiation. Here, we establish differential expression patterns for several Notch receptors and ligands in normal human skin. These immunolocalization findings, together with functional studies demonstrating increased levels of Notch ligand/receptors occurring during the onset of differentiation, prompted use of a soluble Notch ligand, a peptide derived from the most conspicuously expressed ligand in skin, Jagged-1. Exposing submerged KC monolayers to this peptide (JAG-1) in co-presence of elevated calcium ion concentration, produced stratification with loricrin expression. Using a living human epidermal equivalent (EE) model system, when submerged cultures were raised to an air/liquid interface to generate a fully mature epidermis, activation of Notch signaling was detected. Addition of JAG-1 peptide to submerged EEs was sufficient to induce epidermal maturation. Moreover, a soluble decoy Notch inhibitor prevented such differentiation and corneogenesis in human EEs exposed to either an air/liquid interface or to the JAG-1 peptide. In KC monolayers, addition of JAG-1 peptide induced IKKalpha mediated NF-kappaB activation, as well as increased PPARgamma expression. Immunoprecipitation/Western blot analysis revealed a physical association between the p65 subunit of NF-kappaB and PPARgamma. These results indicate that activation of Notch signaling is necessary for maturation of human epidermis, and activation by a soluble Notch ligand is sufficient to trigger complete KC differentiation including cornification.
Adult↗
Review article: breath testing for human liver function assessment.
Carbon-labelled breath tests were proposed as tools for the evaluation of human liver function 30 years ago, but have never become part of clinical routine. One reason for this is the complex role of the liver in metabolic regulation, making it difficult to provide essential information for the management of patients with liver disease with a single test and to satisfy the hepatology community. As a result, a battery of breath tests have been developed. Depending on the test compound administered, different metabolic pathways (microsomal, cytosolic, mitochondrial) can be examined. Most available data come from microsomal function tests, whilst information about cytosolic and mitochondrial liver function is more limited. However, breath tests have shown promise in some studies, in particular to predict the outcome of patients with chronic liver disease or to monitor hepatic function after treatment. Whilst we await new substrates that can be used to measure liver function in a more valid manner, and large prospective studies to assess the usefulness of available test compounds, the aim of this review is to describe how far we have come in this controversial and unresolved issue.
Breath Tests↗
Prescribing second-generation antipsychotics and the evolving standard of care in Italy.
The present study was carried out to investigate the routine use of second-generation antipsychotic drugs in the Italian psychiatric care system. Seven outpatient psychiatric services enrolled a consecutive case series of patients who were being treated, or had started treatment, with clozapine, olanzapine, risperidone, or quetiapine. Information on sociodemographic and clinical variables, current psychotropic drug use, side-effects and past use of typical drugs was collected. In addition, patient symptoms and functional status were evaluated by the Health of the Nation Outcome Scale. Patients receiving off-label prescribing of second-generation antipsychotics were identified. A total of 209 patients were collected. In comparison with patients receiving other second-generation antipsychotics, living in residential facilities, unemployment, long psychiatric histories, and problems with activities of daily living and living conditions were more common in clozapine-treated patients. Nearly 80 % of patients receiving clozapine had schizophrenia compared to less than 50 % of those receiving other second-generation antipsychotics. Overall, 109 patients (52 %) received off-label prescriptions of second-generation antipsychotic drugs. This survey indicates that clozapine was mostly reserved for severe cases and poor responders; the high rate of off-label prescriptions highlights the gap existing between recommendations derived from randomised clinical trials and the current use of drugs.
Adolescent↗
Gastrointestinal stromal tumor (GIST) and ulcerative colitis.
A 57 year old woman, affected by Ulcerative Colitis (UC) in remission, was admitted to our unit with a history of episodic melena and progressive anemia. Computed tomography (CT) of the abdomen revealed a solid mass in the upper left pelvic cavity. After surgical laparotomy, the mass showed histological characteristics of a gastro intestinal stromal tumor. This report describes a GIST in a patient with extensive UC, which was in remission at the time of diagnosis. To our knowledge, this is the first report of an association of this type.
Anemia↗
Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells.
We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-kappaB. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-kappaB as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-kappaB-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-kappaB family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-kappaB activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSF-dependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-kappaB. B cells from Notch-AS-Tg mice had almost 3-fold lower response to LPS than B cells isolated from control mice. Differentiation of dendritic cells was significantly affected in Notch-AS-Tg mice. However, it was restored by transduction of activated Notch-1 into HPC. Taken together, these data indicate that in HPC NF-kappaB activity is regulated by Notch-1 via transcriptional control of NF-kappaB.
Animals↗
Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.
The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21WAF1/Cip1 expression, and activated Notch1 causes growth suppression by inducing p21WAF1/Cip1 expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21WAF1/Cip1 expression and early differentiation markers occur through two different mechanisms. The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription. Expression of early differentiation markers is RBP-Jkappa-independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.
Animals↗
Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain.
Notch participates in diverse cell fate decisions throughout embryonic development and postnatal life. Members of the NF-kappaB/Rel family of transcription factors are involved in the regulation of a variety of genes important for immune function. The biological activity of the NF-kappaB transcription factors is controlled by IkappaB proteins. Our previous work demonstrated that an intracellular, constitutively active form of human Notch-1/translocation-associated Notch homologue-1 (Notch(IC)) functions as an IkappaB molecule with specificity for the NF-kappaB p50 subunit and physically interacts with NF-kappaB in T cells. In the current study, we investigated the roles of different domains of Notch(IC) in the regulation of NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. We found that Notch(IC) localizes to the nucleus and that a region in the N-terminal portion of Notch(IC), not the six ankyrin repeats, is responsible for the inhibitory effects of Notch on NF-kappaB-directed gene expression and NF-kappaB DNA binding activity. The N-terminal portion of Notch(IC) inhibited p50 DNA binding and interacted specifically with p50 subunit, not p65 of NF-kappaB. The interaction between Notch and NF-kappaB indicates that in addition to its role in the development of the immune system, Notch-1 may also have critical functions in the immune response, inflammation, viral infection, and apoptosis through control of NF-kappaB-mediated gene expression.
Amino Acid Sequence↗
Non-alcoholic steatohepatitis induced by carbamazepine and variegate porphyria.
A 42-year-old woman presented with acute bullous skin lesions and angio-oedema that had developed 3 months after initiation of treatment with carbamazepine for epilepsy. Chromatographic analysis of urinary porphyrins was compatible with variegate porphyria. This was manifested initially by neurological symptoms that were mistaken for epilepsy and later by cutaneous symptoms also. Histological findings excluded hepatic porphyria, but revealed severe fatty changes thought to be caused by idiosyncratic metabolism of carbamazepine. While the porphyrinogenicity of carbamazepine is well known, the presence of variegate porphyria has not been reported. The toxic hepatic effects of the drug on hepatic cytochrome P-450, which is involved in haem metabolism, could have aggravated the pre-existent porphyria, provoking the onset of skin lesions.
Adult↗
Sporadic HEV hepatitis in Italy.
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Acute Disease↗
Is coeliac disease a confounding factor in the diagnosis of NASH?
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Adult↗