Determinants of troponin T and I elevation in old patients without acute coronary syndrome

Cardiac troponins T and I (cTnT and cTnI) are the main markers of acute myocardial cell damage and then of Acute Coronary Syndrome (ACS) if associated with compatible symptoms. Although their cardio-specificity, the cTn may be increased in various clinical conditions but only few recent studies have reported their trends with age. This is a single-center retrospective observational study on two groups of adults consecutive patients, with age ≥65 years, admitted to the Emergency Department of the Sant'Orsola-Malpighi Hospital of Bologna, Italy, with chest pain as chief complaint. In the first group was dosed cTnT (N=617), in the second group cTnI (N=569). The patients with final ACS’s diagnosis (N=255) or an incomplete report of blood tests (N=17) were excluded. The definitive database included 471 patients in the first group and 443 in the second one. The observed differences between clinical parameters, patients with cTnT≤14ng/L and those with cTnT>14ng/L (N=207, 44%) are: older age, greater prevalence of diabetes, lower values of Hb e ALT, higher values of white blood cells, INR, glycemia, urea, creatinine, BNP e PCR. In multiple logistics regression (N=333) only 4 variables resulted independently associated to cTnT increase: age (P40ng/L (N=46, 10%) are: older age, Hb values equal and higher values of white blood cells, INR, glycemia, urea, creatinine, total bilirubin, AST, BNP e PCR. In multiple logistics regression (N=259) the only 4 variables independently associated to increase of cTnI are age (P<0.0001), glycemia (P=0.004), PCR (P=0.01) and white blood cells (P=0.02), R2=0.17. Furthermore, the number of patients with high level of cTn significantly increase by age (cTnT: 65-74 years 22.2%, 75-84 years 48.5%, ≥85 years 79.5%; cTnI: 65-74 years 4.3%, 75-84 years 8.1%, ≥85 years 22.5%, P<0.0001). In our study, cTnI showed fewer false positives than cTnT and seems to be less influenced by kidney failure. Furthermore, the acute phase of inflammation was associated with the rise of troponins. High cTn values were found in elderly subjects, without acute coronary syndromes, particularly cTnT. Then the age seems to be the most important factor related to this highelevated troponin levels

Ectopic expression of CXCL13, BAFF, APRIL and LT-ß is associated with artery tertiary lymphoid organs in giant cell arteritis

Objectives To investigate whether artery tertiary lymphoid organs (ATLOs) are present in giant cell arteritis (GCA) and that their formation is associated with the ectopic expression of constitutive lymphoid tissue-homing chemokines. Methods Reverse transcriptase PCR, immunohistochemical and immunofluorescence analysis were used to determine the presence of ectopic ATLOs in GCA and the expression of chemokines/chemokine receptors and cytokines involved in lymphoneogenesis in the temporal artery samples obtained from 50 patients with GCA and 30 controls. The presence of lymphatic conduits, of follicular dendritic cells (FDCs) precursors and lymphoid tissue inducer cells was also investigated. Finally, expression of CXCL13, B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and CCL21 by isolated myofibroblasts was evaluated before and after stimulation with Toll-like receptors (TLRs) agonists and cytokines. Results ATLOs were observed in the media layer of 60% of patients with GCA in close proximity to high endothelial venules and independently by the age of patients and the presence of atherosclerosis. ATLO formation was also accompanied by the expression of CXCL13, BAFF, a proliferation-inducing ligand (APRIL), lymphotoxin (LT)-ß, interleukin (IL)-17 and IL-7, the presence of FDC precursors and of lymphoid conduits. Stimulation of myofibroblasts with TLR agonists and cytokines resulted in the upregulation of BAFF and CXCL13. Conclusions ATLOs occur in the inflamed arteries of patients with GCA possibly representing the immune sites where immune responses towards unknown arterial wall-derived antigens may be organised

Increased expression of interleukin-22 in patients with giant cell arteritis

GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis

New insights into the pathogenesis of giant cell arteritis

Giant cell arteritis (GCA) is an inflammatory chronic disease occurring exclusively in elderly individuals. Until recently, the disease has been considered a unique disease resulting from the interaction in the walls of susceptible arteries, between an unknown infectious agents with local dendritic cells (DCs), activated CD4 T cells and effector macrophages. Recent evidence has shown that this view was too simplistic and has clarified many of the pathogenetic aspects of the disease. Many genetic studies recently published have identified different new genes, including cytokines, adhesion molecules and regulators of innate immunity, as crucial players in the development and progression of GCA. Recent evidence suggests that there is heterogeneity of histological lesions in GCA, that are correlated with different immunological Th9 and Th17 signature. The recent demonstration that Varicella-zoster virus (VZV) antigen is present in the 64% of GCA-negative TAs and in the 73% of GCA-positive TAs could represent an important point of arrival in the search for a causative agent in the pathogenesis of a metameric disease such as GCA. In this context, cytokines such as IL-32 and IL-33 that act as a danger signal following tissue damage and infection are over-expressed in GCA arteries. Artery tertiary lymphoid organs, present in up to 50% of GCA-positive arteries, could represent the sites were primary immune responses and T- and B-cell autoimmune responses against viral antigens are organized. The recently demonstrated disturbed distribution of B cells in GCA could be also relevant in the pathogenesis of the disease, possibly contributing to the enhanced IL-6 response. Altogether, these evidences may clarify many pathogenetic aspect of the disease, also suggesting complexity greater than first imagined

An Unusual Cause Of Alveolar Accumulation Of Foamy Macrophages In Adults

A 33-year-old non-smoking female presented with a 6-months history of mild dyspnea and cough. Physiologic testing showed a moderate restrictive ventilatory impairment, whereas high-resolution CT revealed bilateral ground-glass opacities and thickening of interlobular septa. A videothoracoscopic biopsy was performed. Microscopically, the pulmonary architecture was preserved, with only a minimal interstitial fibrosis. The alveolar and the bronchiolar spaces were filled by finely vacuolated macrophages, whereas Pas-positive macrophages expanded the pleural and the interlobular connective tissues. The bronchiolar epithelium had a peculiar clear cytoplasm. Three months after the biopsy, the patient presented with abdominal pain, hepatosplenomegaly and thrombocytopenia. A bone marrow biopsy showed a \u201csea-blue histiocytosis\u201d. The sphingomyelinase activity, evaluated in cultured fibroblasts, was markedly reduced and a diagnosis of Niemann-Pick disease type B was performed. In the lung: 1) the evaluation of both morphology and localization of the macrophages may provide useful diagnostic clues to the pathologist; 2) although rare, the possibility of a metabolic disease must be considered also in adults; and 3) a diffuse alveolar accumulation of foamy macrophages without a significant fibrosis/inflammation, particularly when associated with a clarification of the bronchiolar epithelium, is characteristic of pulmonary involvement in Niemann-Pick disease

CARCINOMA MUCOEPIDERMOIDE SCLEROSANTE CON EOSINOFILIA E “NIDI CELLULARI SOLIDI” DELLA TIROIDE. STUDIO IMMUNOISTOCHIMICO

Il carcinoma mucoepidermoide sclerosante con eosinofilia (CMSE) della tiroide è una neoplasia rara, la cui origine è tuttora dibattuta. La presenza di una differenziazione squamosa in questo tumore, ha fatto avanzare l’ipotesi di un’origine dai cosiddetti “nidi cellulari solidi” (NCS), piccoli aggregati cellulari con aspetti squamoidi e , talora cistici, che sono ritenuti essere residui del corpo ultimobrachiale. Allo scopo di acquisire nuove informazioni sul CMSE e sulla sua eventuale correlazione con i NCS, abbiamo studiato 2 casi di CMSE e ne abbiamo confrontato morfologia e immunofenotipo con una serie di 14 NCS tiroidei. Tra questi, 8 presentavano aspetti cistici piu’ o meno marcati con evidenza di mucosecrezione, prevalentemente di tipo neutro (PAS positiva). Tutti i casi sono stati testati con anticorpi anti TTF1, anti-p63, anti citocheratina 19 e anti MUC 2, 5,6. Inoltre con gli stessi anticorpi sono stati testati anche 2 CMSE. Nella nostra serie, i due casi di CMSE hanno mostrato un immunofenotipo simile, anche se non identico, ai NCS. Infatti entrambi i CMSE e tutti i NCS sono risultati positivi con p63 e citocheratina 19. Il TTF1 è risultato focalmente positivo nella componente ghiandolare dei CMSE e negativo in quella squamoide, mentre nei NCS lo stesso anticorpo ha decorato in 3 casi rare cellule della componente cistica-ghiandolare. Anche con gli anticorpi anti-MUC i risultati sono stati simili: il secreto della componente cistica e rare cellule in 6 casi di NCS sono risultati positivi con anti MUC 6, cosi’ come nei due casi di CME, mentre MUC 2 e 5 sono risultati negativi in tutti i casi. Anche se sarà necessario confermare i dati con lo studio di un numero maggiore di CMSE, i nostri risultati sembrano supportare l’ipotesi di un’origine comune per questo tumore e i NCS tiroidei

Microsatellite and EGFR, HER2 and K-RAS analyses in sclerosing hemangioma of the lung.

Sclerosing hemangioma (SH) is an uncommonpulmonary tumor thought to derive from primitive respiratoryepithelium consisting of 2 cell populations (cuboidal surface andpolygonal stromal cells) and sharing some clinical characteristics(frequent occurrence in nonsmoking women of Asian ethnicity)with bronchioloalveolar carcinoma with which it has beensuggested a possible common origin. We investigated 11 cases ofSH by immunohistochemistry, fluorescence in situ hybridization,and polymerase chain reaction-based microsatellite andmutational analyses with particular emphasis on possiblealterations of microsatellite loci located at tumor suppressorgenes (FHIT, p16, Rb, and p53) involved in lung adenocarcinomagenesis and EGFR, HER2, and K-RAS genes. AlthoughEGFR expression was observed in all tested cases, none showedHER2 immunostaining. Fluorescence in situ hybridization andmutational analysis of EGFR and HER2 and also K-RASsequencing did not reveal molecular alterations, whereas alleliclosses at p16 and Rb loci (4 and 2 out of 9 tested cases,respectively) with an identical microsatellite allelic loss patternin both cuboidal and polygonal cells were observed. The findingof microsatellite alterations in chromosomal regions related togenes deeply involved in early stage lung adenocarcinoma couldsuggest a possible link between SH and bronchioloalveolarcarcinoma, but tumor pathway promoted by EGFR, HER2, andK-RAS does not represent a common molecular mechanism oftumorigenesis. Microsatellite alterations identified in cuboidaland polygonal cells further confirm the clonal and neoplasticnature of both components of SH

Nasal seromucinous hamartoma (Microglandular adenosis of the nose): A morphological and molecular study of five cases

Five cases of nasal seromucinous hamartoma were studied and their clinical, morphological, immunohistochemical and molecular data are reported. The patients, three females and two males, ranged in age from 49 to 66 years (mean 56 year, SD ± 7.91). All lesions were located in the nasal cavity. In four cases where follow-up was obtained, no recurrence was evident. In all cases, numerous small seromucinous tubules, embedded in a cellular stroma, were present in the lamina propria. Tubules were lined by one layer of cuboidal cells which displayed luminal phenotype positive for lysozyme and EMA in four, and S100 protein in all cases. Collagen IV and laminin positive basal lamina outlined the tubules which lacked basal cells. Stromal spindle cells present among tubules were immunoreactive for calponin in all cases and for alpha-smooth muscle actin in four cases. DNA mutation analysis of mitochondrial D-loop region was performed by direct sequencing in order to verify the mutation rate of these lesions. The tubules of the five seromucinous hamartomas showed a higher mutation rate especially in heteroplasmy (0.52% homoplasmy, 2.02% heteroplasmy) in comparison to normal seromucinous glands which exhibited a lower mutation frequency (0.83%). This is considered a sign of a low cellular proliferation rate consistent with a benign process. It is concluded that nasal seromucinous hamartomas are benign glandular proliferations that may resemble microglandular adenosis of the breast. Their distinction from benign and malignant mimics is discussed

Avidin\u2013biotin system: a small library of cysteine biotinylated derivativesdesigned for the [99mTc(N)(PNP)]2+ metal fragment

Using the avidin\u2013biotin system as model, we investigate here the effective application of [Tc(N)L(PNP)]+/0 technology (L=Nfunctionalized cysteine [O-,S-]; PNP=aminodiphosphine) to the preparation of target-specific radiopharmaceuticals. A series of 99mTc-nitrido complexes containing functionalized biotin ligands was prepared and their biological profile was determined. To minimize the steric and the electronic influences of the Tc-carrying complex on the biotin\u2013avidin receptor interaction, the following N-functionalized cysteine\u2013biotin derivatives were synthesized: (1) Biot-CysOSH; (2) Biot-Abu-CysOSH; (3) Biot-Abz-CysOSH; (4) Biot-L- (Ac)Lys-CysOSH; (5) Biot-D-(Ac)Lys-CysOSH; (6) Biot-Glu-CysOSH. The asymmetrical nitrido-Tc(V) 99g/99mTc(N)(Biot-X-CysOS)(PNP3) (X=spacer) complexes, where PNP3 was N,N-bis-[(dimethoxypropyl) phosphinoethyl] methoxy-ethylamine, were obtained by simultaneous addition of PNP3 and the relevant biotinylated ligand to a solution containing a 99mTc-nitrido precursor (yields N95%). In all cases, a mixture of syn- and anti isomers was observed. In vitro challenge experiments with glutathione and cysteine indicated that no transchelation reactions occurred. Assessment of the in vitro binding to avidin of the complexes revealed that only the complexes containing Biot-Abu-CysOS and Biot-Glu-CysOS ligand maintained a good affinity for the concentrator. Stability studies carried out in human and mouse plasma as well as in rat and mouse liver homogenate evidenced a rapid enzymatic degradation for the 99mTc(N)(Biot-Abu-CysOS)(PNP3) complex, whereas the 99mTc(N)(Biot-Glu-CysOS)(PNP3) one was stable in all conditions. Tissue biodistribution in normal Balb/C mice of the most stable candidate showed a rapid clearance both from the blood and the other tissues. The activity was eliminated both through the hepatobiliary system and the urinary trac