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This systematic review examine the biological effects of CBD, a major component of therapeutic Cannabis, on human pathological and cancer cell populations of integumentary, gastro-intestinal, genital and breast, respiratory, nervous, haematopoietic and skeletal districts in terms of cell viability, proliferation, migration, apoptosis, inflammation, metastasis, and CBD receptor expression. The included studies were in English, on human cell lines and primary culture from non-healthy donors with CBD exposure as variable and no CBD exposure as control. Quality assessment was based on ToxRtool with a reliability score ranging from 15 to 18. Following the PRISMA statement 4 independent reviewers performed an electronic search using MEDLINE via PubMed, Scopus and Web of Science. From 3974 articles, 83 studies have been selected. Data showed conflicting results due to different concentration exposure, administrations and time points. CBD inhibited cell viability and proliferation in most cellular districts except the integumentary apparatus. Also a significant inhibition of migration was observed in all cell types, while an increase in apoptosis at both high and low doses (greater and less than 10 μM respectively). Considering inflammation, CBD caused an anti-inflammatory effect on nervous cells at low doses and on gastro-intestinal cells at high doses, while metastatic power was reduced even at low doses, but in a skeletal cell line there was an increased angiogenesis. CB1 receptor has been related to viability effects, CB2 to apoptosis and TRPV1 to inflammation and invasiveness. A detailed insight into these aspects would allow therapeutic use of this substance without possible side effects., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to document the evolution of cranial asymmetries in infants with signs of nonsynostotic occipital plagiocephaly (NSOP) who underwent to many functional manual therapy treatments (in addition to the standard positioning recommendations); as well as to determine the feasibility of this methodology to conduct outcome research investigating the impact of this intervention for infants with NSOP., Methods: This is a pilot clinical standardization project using pre-post design in which 10 infants participated. Nine infants presented an initial Oblique Diameter Difference Index (ODDI) (over 104%), three an initial Ear Deviation Index (EDI) (over 4%), and three a Cranial Proportional Index (CPI) (over 90%). Infants received three functional manual therapy treatments for week during the first month of intervention and two for week during the second month., Results: Plagiocephalometric measurements were administered at the first assessment preintervention (T0), after 30 days (±5) (T1) and at a third time after 60 days (±5) of treatment (T2). Nine out of ten participants showed a significant decrease in ODDI under 104% between T0 and T2 assessments. Five out of ten infants showed an EDI under 4%, and 3/10 showed a value about 0%. 3/10 maintained their CPI over 90% with a considerable decrease., Conclusions: These clinical findings support the hypothesis that functional manual therapy treatments contribute to the improvement of cranial asymmetries in infants younger than 6.5 months old presenting with NSOP.

Objectives: The aim of this work is to investigate the biological effects of IQOS smoking on human gingival fibroblasts and human keratinocytes analysing cell viability, morphology, migration, apoptosis and cell cycle., Background: Electronic cigarettes and tobacco heating systems have been marketed to reduce smoking damages caused by combustion., Methods: Human gingival fibroblasts and human keratinocytes viability was determined by a colorimetric assay measuring mitochondrial dehydrogenase activity (MTT assay); after an in vitro exposure of 24 h, cell morphology was analysed with scanning electron microscope and cell migration was tested by Scratch assay, a method to mimic the migration of the cells during wound healing in vivo. Apoptosis and cell cycle were analysed with flow cytometry, and the expression of related genes (p53, Bcl2, p16 and p21) was indagated using real-time polymerase chain reaction., Results: IQOS extracts increased both cell viability (23%-41% with fibroblasts and 30%-79% with keratinocytes) and migration. No morphological alterations were observed. IQOS extracts did not induced an increase in cell death, but rose the number of S- and G2/M-phase cells. IQOS extracts also significantly increased p53 expression by fibroblasts (undiluted and 6.25% dilution, 2- and 3.6-fold higher, respectively) and reduced both Bcl2 (about two- and fivefold, respectively) and p21 expressions (about twofold with both extracts), while on keratinocytes both undiluted and 6.25% dilution extracts increased Bcl2 expression (about four- and threefold higher, respectively) and reduced p53 expression (about two- and fivefold, respectively)., Conclusion: IQOS smoke seemed to induce proliferation as highlighted by a viability assay, and migration and cell cycle analysis. The increased cell proliferation induced by IQOS devices must be carefully investigated for its possible clinical effects on oral cell populations., (© 2021 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd.)

Background: The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue mainly characterized by joint hypermobility. Patients with hEDS suffer joint pain, in particular low back pain, commonly resistant to drug therapy. The aim of this research was to evaluate a neurocognitive rehabilitation approach based not only on the motion and function recovery but also on the pain management., Methods: In this nonrandomized clinical trial, eighteen hEDS patients (4 males and 14 females) with mean age 21 years (range 13-55) were recruited and evaluated before and after three months of rehabilitation treatment., Results: The outcome scores showed significant statistical results after treatment in reducing pain symptoms (numerical rating scale, P = 0.003; McGill (total score), P = 0.03), fatigue (fatigue severity scale, P = 0.03), fear of movement (Tampa scale, P = 0.003), and pain-associated disability (Oswestry disability index, P = 0.03)., Conclusion: The clinical results observed in our study seem to confirm the role of a specific neurocognitive rehabilitation program in the chronic pain management in the Ehlers-Danlos syndrome; the rehabilitation treatment should be tailored on patient problems and focused not only in the recovery of movement but also on pain perception., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Claudia Celletti et al.)

Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of 84 circulating microRNAs (miRNAs) in 182 patients with resected early-stage NSCLC (99 adenocarcinoma (ADC), 83 squamous cell carcinoma (SCC)) from whom peripheral blood samples were collected pre-surgery. miRNA expression was analyzed in relation to disease-free survival (DFS) and overall survival (OS). In univariable analyses, five miRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p) were significantly associated with DFS in SCC, and four (miR-130b-3p, miR-26a-5p, miR-126-3p, and miR-205-5p) remained significantly associated with OS. In ADC, miR-222-3p, miR-22-3p, and mir-93-5p were significantly associated with DFS, miR-22-3p remaining significant for OS. Given the high-dimensionality of the dataset, multivariable models were obtained using a regularized Cox regression including all miRNAs and clinical covariates. After adjustment for disease stage, only miR-126-3p showed an independent prognostic role, with higher values associated with longer DFS in SCC patients. With regard to ADC and OS, no miRNA remained significant in multivariable analysis. Further investigation into the role of miR-126 as a prognostic marker in early-stage NSCLC is warranted.

The aim of this consensus conference was to provide clinical guidelines, based on the available evidence and on the author's daily practice and experience, for general dentistry and dental practitioners to allow them to delivery long-term successful restorations. Three groups of expert clinicians and dental technicians were invited to evaluate all of the scientific literature from 1967 up to March 2017 to identify relevant studies on assigned topics and to prepare in advance narrative/systematic review, written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, to fulfill the consensus statement criteria. The three topics assigned to the three groups were abutment/framework materials and customization (metal vs. metal-free restorations), abutment/framework protocols and designs, and abutment/framework retentions (cemented- vs. screw-retained implant-supported prostheses). All the expert clinicians presented their results, and the lectures were followed by discussions. No significant differences in clinical parameters (marginal bone loss, bleeding on probing, and pocket probing depth) between screw- or cemented-retained were found for single and multiple implant-supported restorations. There is moderate evidence that nonoriginal abutments provide worse mechanical behavior than originals and high evidence that different implant neck designs do not offer any clinical or radiographic advantage. All the participants agreed that it is desirable to connect and remove abutments as few times as possible. There is medium evidence that an adequate platform switching tends to enhance tissue volume and stability in the medium- and long-term follow-up. No statistically significant differences exist between metal and zirconia as a framework material. The authors discussed and all agreed that retrievability and patient's expectation (function and esthetics) should guide the choice of the most adequate technique, component, and material., Competing Interests: There are no conflicts of interest.

In cancer cells, global genomic hypomethylation is found together with localized hypermethylation of CpG islands within the promoters and regulatory regions of silenced tumor suppressor genes. Demethylating agents may reverse hypermethylation, thus promoting gene re-expression. Unfortunately, demethylating strategies are not efficient in solid tumor cells. DNA demethylation is mediated by ten-eleven translocation enzymes (TETs). They sequentially convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is associated with active transcription; 5-formylcytosine; and finally, 5-carboxylcytosine. Although α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid, the major n-3 polyunsaturated fatty acids, have anti-cancer effects, their action, as DNA-demethylating agents, has never been investigated in solid tumor cells. Here, we report that EPA demethylates DNA in hepatocarcinoma cells. EPA rapidly increases 5hmC on DNA, inducing p21 Waf1/Cip1 gene expression, which slows cancer cell-cycle progression. We show that the underlying molecular mechanism involves TET1. EPA simultaneously binds peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα), thus promoting their heterodimer and inducing a PPARγ-TET1 interaction. They generate a TET1-PPARγ-RXRα protein complex, which binds to a hypermethylated CpG island on the p21 gene, where TET1 converts 5mC to 5hmC. In an apparent shuttling motion, PPARγ and RXRα leave the DNA, whereas TET1 associates stably. Overall, EPA directly regulates DNA methylation levels, permitting TET1 to exert its anti-tumoral function.-Ceccarelli, V., Valentini, V., Ronchetti, S., Cannarile, L., Billi, M., Riccardi, C., Ottini, L., Talesa, V. N., Grignani, F., Vecchini, A., Eicosapentaenoic acid induces DNA demethylation in carcinoma cells through a TET1-dependent mechanism.

Epigenetic alterations, including aberrant DNA methylation, contribute to tumor development and progression. Silencing of tumor suppressor genes may be ascribed to promoter DNA hypermethylation, a reversible phenomenon intensely investigated as potential therapeutic target. Previously, we demonstrated that eicosapentaenoic acid (EPA) exhibits a DNA demethylating action that promotes the re-expression of the tumor suppressor gene CCAAT/enhancer-binding protein δ (C/EBPδ). The C/EBPβ/C/EBPδ heterodimer formed appears essential for the monocyte differentiation commitment. The present study aims to evaluate the effect of EPA on RAS/extracellular signal regulated kinases (ERK1/2)/C/EBPβ pathway, known to be induced during the monocyte differentiation program. We found that EPA conditioning of U937 leukemia cells activated RAS/ERK/C/EBPβ pathway, increasing the C/EBPβ and ERK1/2 active phosphorylated forms. Transcriptional induction of the upstream activator H-Ras gene resulted in increased expression of H-Ras protein in the active pool of non raft membrane fraction. H-Ras gene analysis identified an hypermethylated CpG island in intron 1 that can affect the DNA-protein interaction modifying RNA polymerase II (RNAPII) activity. EPA treatment demethylated almost completely this CpG island, which was associated with an enrichment of active RNAPII. The increased binding of the H-Ras transcriptional regulator p53 to its consensus sequence within the intronic CpG island further confirmed the effect of EPA as demethylating agent. Our results provide the first evidence that an endogenous polyunsaturated fatty acid (PUFA) promotes a DNA demethylation process responsible for the activation of RAS/ERK/C/EBPβ pathway during the monocyte differentiation commitment. The new role of EPA as demethylating agent paves the way for studying PUFA action when aberrant DNA methylation is involved.

The aim of the present study was to evaluate the importance of a multidisciplinary approach on increasing the response ratio expectation to mandibular advancing device (MAD) therapy in patients with obstructive sleep apnoea syndrome, especially in severe cases. Forty-two mild-to-severe OSAS patients were selected, after comprehensive evaluation by neurologists, otorhinolaryngologists and orthodontists, and treated with a Somnodent® device. Six months later, a polysomnographic exam with the MAD in situ was performed. The paired t-test evaluated the effectiveness of therapy and the results were compared with data from systematic reviews. The average treatment response was statistically significant for the apnoea/hypopnea index (AHI) and oxygen desaturation index and was higher than the outcomes presented in literature. An optimum therapy response (AHI < 5) was observed in 53% of patients (40% in severe OSAS) and a good response (AHI < 10) in 73% of patients (50% in severe OSAS). The Somnodent® device was effective and the multidisciplinary patient selection improved the response ratio compared to that reported by previous systematic reviews.

Advances in the understanding of the epigenetic events underlying the regulation of developmental genes expression and cell lineage commitment are revealing novel regulatory networks. These also involve distinct components of the epigenetic pathways, including chromatin histone modification, DNA methylation, repression by polycomb complexes and microRNAs. Changes in chromatin structure, DNA methylation status and microRNA expression levels represent flexible, reversible and heritable mechanisms for the maintenance of stem cell states and cell fate decisions. We recently provided novel evidence showing that microRNAs, besides determining the post-transcriptional gene silencing of their targets, also bind to evolutionarily conserved complementary genomic seed-matches present on target gene promoters. At these sites, microRNAs can function as a critical interface between chromatin remodeling complexes and the genome for transcriptional gene silencing. Here, we discuss our novel findings supporting a role of the transcriptional chromatin targeting by polycomb-microRNA complexes in lineage fate determination of human hematopoietic cells.

Statement of Problem: Immediate occlusal loading of dental implants in the edentulous mandible has proven to be an effective, reliable, and predictable treatment protocol. However, there is limited long-term data available in the literature, when an electroeroded definitive cast-titanium fixed prosthesis is used for this treatment protocol., Purpose: The aim of this study was to evaluate the clinical effectiveness of dental implants (Astra Tech Dental, Mölndal, Sweden) in the edentulous mandible immediately loaded with an electroeroded cast-titanium screw-retained fixed prosthesis., Materials and Methods: Forty-five patients received five implants each in the interforaminal area. All the implants were inserted with torque up to 40 Ncm and the distal implants were distally tilted approximately 20 to 30 degrees to minimize the length of posterior cantilevers. Implants were loaded within 48 hours of placement with an acrylic resin-titanium screw-retained prosthesis fabricated by electroerosion., Results: Two of the 225 inserted implants failed after 3 and 16 months of healing, respectively, with a cumulative survival rate of 99.1% and a prosthetic survival rate of 97.8%., Conclusion: Immediate loading of tilted dental implants inserted in the edentulous mandible with a screw-retained titanium definitive prosthesis fabricated with electrical discharge machining provide reliable and predictable results., (© 2011 Wiley Periodicals, Inc.)

Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a posttranscriptional microRNA-223 (miR-223) target directing human hematopoietic progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin "bivalent domains," hypermethylation, recruitment of polycomb (PcG)-RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.

An epidemiological survey for canine parvovirus (CPV) and canine coronavirus (CCoV) infections was conducted in Western Europe. A total of 156 faecal samples were collected from dogs with diarrhoea in Spain (n=47), Italy (n=39), France (n=26), Germany (n=21), the United Kingdom (n=8), Belgium (n=10), and the Netherlands (n=5). Using molecular assays for virus detection and characterisation, CPV and CCoV were found to be widespread in European dog populations, either alone or in mixed infections. In agreement with previous reports, the original type CPV-2 was shown not to circulate in European dogs. The recently identified virus variant CPV-2c was predominant in Italy and Germany and present at high rates in Spain and France but was not detected in the UK or Belgium. Except for the UK, CCoV genotype I was identified in all European countries involved in the survey, albeit at a lower prevalence rates than CCoV genotype II., (Copyright © 2009 Elsevier Ltd. All rights reserved.)

Estrogen receptors (ERs) are a recognized prognostic factor and therapeutic target in breast cancer. The loss of ER expression relates to poor prognosis, poor clinical outcome and impairs the use of anti-estrogenic treatment. Histone deacetylase inhibitors are candidate drugs for cancer therapy. Among them, valproic acid (VPA) is a long used and safe anti-epileptic drug. We studied the biological consequences of the chromatin remodeling action of VPA in a normal human mammary epithelial cell line and in ERalpha-positive and ERalpha-negative breast cancer cell lines. In these cells and regardless of their ER status, VPA-induced cell differentiation, as shown by increased milk lipids production, decreased expression of the CD44 antigen and growth arrest in the G(0)-G(1) phase of the cell cycle. These effects were accompanied by decreased Rb phosphorylation, hyperacetylation of the p21(WAF1/CIP1) gene promoter and increased p21 protein expression. Only in breast cancer cells, cyclin B1 expression was decreased and the cells accumulated also in G(2). ERalpha expression decreased in ERalpha-positive, increased in ERalpha-negative and was unchanged in normal mammary epithelial cells, as did the expression of progesterone receptor, a physiological ERalpha target. VPA decreased the expression of the invasiveness marker pS2 in ERalpha-positive breast cancer cells, but did not cause its re-expression in ERalpha-negative cells. Overall, these data suggest that in both ERalpha-positive and -negative malignant mammary epithelial cells VPA reprograms the cells to a more differentiated and "physiologic" phenotype that may improve the sensitivity to endocrine therapy and/or chemotherapy in breast cancer patients.

Objectives: The aim of the present study was to evaluate the outcome of immediate functional loading of implants in single-tooth replacement using two different installation procedures., Material and Methods: One hundred and fifty-one subjects, who required single-tooth rehabilitation in the area of 15-25 and 35-45, were enrolled in eight private clinics in Italy. The implant sites were randomly allocated to one of the following treatment groups. In the control group, in which a standard preparation procedure for implant placement and submerged healing of the implant was used, abutment connection and loading of the implants were performed 3 months after installation. In the test group 1, a standard preparation procedure for the implant placement and immediate functional loading of implant was carried out. In the test 2 group, however, a modified implant installation procedure (osteotome technique) was used followed by immediate functional loading of the implant. Clinical and radiographic examinations were performed at 3 and 12 months of follow-up at all sites., Results: Three implants (5.5%) from the test 2 group (osteotome preparation) and one (2%) from the test 1 group (conventional drill preparation) failed to integrate and were removed one and three months after implant installation. The mean marginal bone loss assessed at 12 months was 0.31 mm (test 1), 0.25 mm (test 2) and 0.38 mm (control) (no statistically significant differences were found between the three treatment groups.), Conclusion: It is suggested that immediate functional loading of implants that are placed with a conventional installation technique and with sufficient primary stability may be considered as a valid treatment alternative in a single-tooth replacement.

MicroRNAs (miRNAs or miRs) regulate diverse normal and abnormal cell functions. We have identified a regulatory pathway in normal megakaryopoiesis, involving the PLZF transcription factor, miR-146a and the SDF-1 receptor CXCR4. In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. In vitro assays showed that PLZF interacts with and inhibits the miR-146a promoter, and that miR-146a targets CXCR4 mRNA, impeding its translation. In megakaryopoietic cultures of CD34(+) progenitors, PLZF was upregulated, whereas miR-146a expression decreased and CXCR4 protein increased. MiR-146a overexpression and PLZF or CXCR4 silencing impaired megakaryocytic (Mk) proliferation, differentiation and maturation, as well as Mk colony formation. Mir-146a knockdown induced the opposite effects. Rescue experiments indicated that the effects of PLZF and miR-146a are mediated by miR-146a and CXCR4, respectively. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation.

Retinoic acid controls hematopoietic differentiation through the transcription factor activity of its receptors. They act on specific target genes by recruiting protein complexes that deacetylate or acetylate histones and modify chromatin status. The regulation of this process is affected by histone methyltransferases, which can inhibit or activate transcription depending on their amino acid target. We show here that retinoic acid treatment of hematopoietic cells induces the expression of BTG2. Overexpression of this protein increases RARalpha transcriptional activity and the differentiation response to retinoic acid of myeloid leukemia cells and CD34+ hematopoietic progenitors. In the absence of retinoic acid, BTG2 is present in the RARalpha transcriptional complex, together with the arginine methyltransferase PRMT1 and Sin3A. Overexpressed BTG2 increases PRMT1 participation in the RARalpha protein complex on the RARbeta promoter, a target gene model, and enhances gene-specific histone H4 arginine methylation. Upon RA treatment Sin3A, BTG2, and PRMT1 detach from RARalpha and thereafter BGT2 and PRMT1 are driven to the cytoplasm. These events prime histone H4 demethylation and acetylation. Overall, our data show that BTG2 contributes to retinoic acid activity by favoring differentiation through a gene-specific modification of histone H4 arginine methylation and acetylation levels.

The AML1/ETO and PML/RARalpha leukemia fusion proteins induce acute myeloid leukemia by acting as transcriptional repressors. They interact with corepressors, such as N-CoR and SMRT, that recruit a multiprotein complex containing histone deacetylases on crucial myeloid differentiation genes. This leads to gene repression contributing to generate a differentiation block. We expressed in leukemia cells containing PML/RARalpha and AML1/ETO N-CoR protein fragments derived from fusion protein/corepressor interaction surfaces. This blocks N-CoR/SMRT binding by these fusion proteins, and disrupts the repressor protein complex. In consequence, the expression of genes repressed by these fusion proteins increases and differentiation response to vitamin D3 and retinoic acid is restored in previously resistant cells. The alteration of PML/RARalpha-N-CoR/SMRT connections triggers proteasomal degradation of the fusion protein. The N-CoR fragments are biologically effective also when directly transduced by virtue of a protein transduction domain. Our data indicate that fusion protein activity is permanently required to maintain the leukemia phenotype and show the route to developing a novel therapeutic approach for leukemia, based on its molecular pathogenesis.

Prosthetic care for mandibular atrophy has raised many difficult problems, particularly in the most severe cases. The solution to most of these problems lies in the use of osteointegrated implants. Good results were obtained by using a small number of implants associated with adjustable overdenture prostheses or, alternatively, by using a larger number of implants (5 or 6) associated with a screw fixed prosthesis with posterior cantilever. Cantilever prostheses can provide support for the mental foramen zones and the posterior zones of the mandibular body where bone resorption is important after application of adjustable plates to the fibromucosa.

The aim of this study was to investigate the behavior of plasma endothelin-1 (ET-1) in 23 patients with acute myocardial infarction, complicated and uncomplicated by left ventricular failure, and treated with and without thrombolytic agents. ET-1 was measured on admission; on days 2, 3, and 5; and again on discharge. In addition, on discharge, ET-1 was correlated with left ventricular systolic function. Left ventricular failure was present, on admission, in 14 patients, whereas the other nine did not have any hemodynamic impairment. On discharge, no patients had left ventricular failure, but 11 had moderate to severe left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) < 40%. Fourteen subjects, matched for age and sex, served as a control group. Compared with the control range, ET-1 was highly elevated on the first day, in both uncomplicated (p < 0.01) and complicated patients (p < 0.001). Then it decreased rapidly in the uncomplicated group, reaching the control range within day 5, whereas in the complicated group it remained significantly elevated in comparison with both the control subjects and the uncomplicated patients, until discharge. ET-1 was not correlated with the peak of creatine-kinase MB isoenzyme in any group. In seven patients submitted to thrombolytic treatment ET-1 was always significantly lower than in the nonthrombolyzed patients (p < 0.05), but the pattern of variation across time was no different. On discharge, the difference in plasma ET-1 between patients with LVEF < 40% and the control group was significant (p < 0.001), as was the difference between patients with and without moderate to severe systolic dysfunction (p < 0.01). ET-1 was closely and inversely correlated with LVEF when patients were considered as a whole (p < 0.001). These results suggest that the ET-1 increase in the early phase of myocardial infarction could be due to an ischemic process, to stress reaction, and to cardiac hemodynamic impairment, and therefore, ET-1 may be a good marker of disease. In the following phase the ET-1, being correlated with LVEF, could be a reliable index of systolic function.

The t(2;5)(p23;q35) translocation associated with CD30-positive anaplastic large cell lymphoma results in the production of a NPM-ALK chimeric protein, consisting of the N-terminal portion of the NPM protein joined to the entire cytoplasmic domain of the neural receptor tyrosine kinase ALK. The ALK gene products were identified in paraffm sections by using a new anti-ALK (cytoplasmic portion) monoclonal antibody (ALKc) that tends to react more strongly than a previously described ALK1 antibody with the nuclei of ALK-expressing tumor cells after microwave heating in 1 mmol/L ethylenediaminetetraacetic acid buffer, pH 8.0. The ALKc monoclonal antibody reacted selectively with 60% of anaplastic large cell lymphoma cases (60 of 100), which occurred mainly in the first three decades of life and consistently displayed a T/null phenotype. This group of ALK-positive tumors showed a wide morphological spectrum including cases with features of anaplastic large cell lymphoma "common" type (75%), "lymphohistiocytic" (10%), "small cell" (8.3%), "giant cell" (3.3%), and "Hodgkin's like" (3.3%). CD30-positive large anaplastic cells expressing the ALK protein both in the cytoplasm and nucleus represented the dominant tumor population in the common, Hodgkin's-like and giant cell types, but they were present at a smaller percentage (often with a perivascular distribution) also in cases with lymphohistiocytic and small cell features. In this study, the ALKc antibody also allowed us to identify small neoplastic cells (usually CD30 negative) with nucleus-restricted ALK positivity that were, by definition, more evident in the small cell variant but were also found in cases with lymphohistiocytic, common, and "Hodgkin's-like" features. These findings, which have not been previously emphasized, strongly suggest that the neoplastic lesion (the NPM-ALK gene) must be present both in the large anaplastic and small tumor cells, and that ALK-positive lymphomas lie on a spectrum, their position being defined by the ratio of small to large neoplastic cells. Notably, about 15% of all ALK-positive lymphomas (usually of the common or giant cell variant) showed a cytoplasm-restricted ALK positivity, which suggests that the ALK gene may have fused with a partner(s) other than NPM. From a diagnostic point of view, detection of the ALK protein was useful in distinguishing anaplastic large cell lymphoma cases of lymphohistiocytic and small cell variants from reactive conditions and other peripheral T-cell lymphoma subtypes, as well as for detecting a small number of tumor cells in lymphohemopoietic tissues. In conclusion, ALK positivity appears to define a clinicopathological entity with a T/null phenotype ("ALK lymphomas"), but one that shows a wider spectrum of morphological patterns than has been appreciated in the past.

An analysis of the available data concerning the events bringing to the completion of the adrenergic function in early life shows the existence of an early response making the detection of MOPEG-SO4 levels in the urine--the foetus and in the new-born. This response isn't the same in the adult and in the infant as in the latter the number of receptors is lower, the prevalent mediator is NA and the receptorial subtype is almost entirely beta. The effector system, on the contrary, is as fully developed in the infant as it's in the adult. Maybe it will be possible in the future to evaluate--through non-invasive methods such as the detection of MOPEG-SO4 levels in the urine--the degree of development of the central simpatoadrenergic system in order to exactly work out perinatal asphyxia and brains congenital injuries.