Evidence for human diabetic cardiomyopathy.

Growing interest has been accumulated in the definition of worsening effects of diabetes in the cardiovascular system. This is associated with epidemiological data regarding the high incidence of heart failure (HF) in diabetic patients. To investigate the detrimental effects both of hyperglycemia and insulin resistance, a lot of preclinical models were developed. However, the evidence of pathogenic and histological alterations of the so-called diabetic cardiomyopathy (DCM) is still poorly understood in humans. Here, we provide a stringent literature analysis to investigate unique data regarding human DCM. This approach established that lipotoxic-related events might play a central role in the initiation and progression of human DCM. The major limitation in the acquisition of human data is due to the fact of heart specimen availability. Postmortem analysis revealed the end stage of the disease; thus, we need to gain knowledge on the pathogenic events from the early stages until cardiac fibrosis underlying the end-stage HF

Strategies and Controversies in the Treatment With Carbon Dioxide Laser of Laryngeal Hemangioma: A Case Series and Review of the Literature

The hemangioma is the most common vascular tumor, involving the head and neck in 60% of cases. It is rare in the larynx. In children, hemangiomas are more frequent on the subglottis, whereas in adults the most common site is the supraglottis. Laryngeal hemangioma with cavernous features isolated to the free edge of the vocal fold is a very rare clinical finding. We present 2 cases of glottic hemangioma. Both patients reported severe hoarseness

The Human MDM2 Oncoprotein Increases the Transcriptional Activity and the Protein Level of the p53 Homolog p63

Genetic alteration of the p53 tumor suppressor gene, which monitors DNA damage and operates cell cycle checkpoints, is a major factor in the development of human malignancies. The p53 protein belongs to a family that also includes two structurally related proteins, p63 and p73. Although all three proteins share similar transcriptional functions and antiproliferative effects, each of them appears to play a distinct role in development and tumor suppression. One of the principal regulators of p53 activity is the MDM2 protein. The interaction of MDM2 with p53 inhibits p53 transcriptional activity and targets p53 for ubiquitin-dependent degradation. The ability of MDM2 to inhibit p53 functions is antagonized by the ARF oncosuppressor protein. We show here that like p53, the p63alpha and p63gamma isoforms are able to associate with human MDM2 (HDM2). Overexpression of HDM2 increased the steady-state level of intracellular p63 and enhanced its transcriptional activity. Both effects appeared to be counteracted by ARF coexpression. These data indicate that p63 can be activated by HDM2 under conditions in which p53 is inhibited. Therefore, HDM2 expression could support p63-specific transcriptional functions on a common set of genes, keeping interference by p53 at a minimum

Autoptic findings of sudden cardiac death (SCD) in patients with arrhythmogenic ventricular cardiomiopathy (AVC) from left ventricle and biventricular involvement.

Objectives: To evaluate autoptic histopathological findings of arrhythmogenic ventricular cardiomyopathy (AVC) as major cause of sudden cardiac death (SCD) in young adults. Background: According to Heart Rhythm Society (HRS)'s international consensus, histological criteria for AVC diagnosis include a progressive myocardial atrophy of the right ventricle characterized by a transmural fatty or fibrofatty replacement in a segmental or diffuse pattern (residual myocytes <60 % vs 60–75 % by morphometric analysis) explaining the electrical instability with increased risk of SCD. However, there is increasing evidence for atypical patterns of localizations and percentage of fibrofatty replacement suggesting the need to update histopathological features of AVC. Methods: Histology examination of ventricles, atria, and septum was performed on 10 autopsy of SCD due to AVC. Staining with hematoxylin-eosin and PicroSirius Red/Fast Green were performed on the heart samples to identify specific fibrofatty patterns. Results: Our analysis showed that: 1) myocardial replacement by a diffuse segmental fatty or fibro-fatty tissue characterized right and left ventricles as well as atrial walls; 2) the degree of fibrofatty tissue replacement was less than 40 % both in left ventricle (n = 4, 40 %) and biventricular (n = 6, 60 %) localization; 3) perivascular fibrosis, inflammatory infiltrate, areas of hypertrophy and/or areas of coagulative necrosis as signs of hypoxic damage in the first stage. Conclusions: We confirmed prior evidence for fibrofatty replacement both in biventricular and septal localizations. Importantly, we observed a less degree (<40 %) of fibrofatty replacement as compared to current guidelines. This supports the need to further explore the histological patterns of fibrofatty infiltration in a larger study population to improve the histological diagnostic criteria of AVC

Strategy for the treatment and follow-up of sinonasal solitary extramedullary plasmacytoma: a case series

Extramedullary plasmacytoma is a rare neoplasm characterized by monoclonal proliferation of plasma cells outside bone marrow. It accounts for 4% of all non-epithelial sinonasal tumors. According to the literature, radiotherapy is the standard therapy for extramedullary plasmacytoma. However, the conversion rate of extramedullary plasmacytoma to multiple myeloma is reported to be between 11 and 33% over 10 years. The highest risk of conversion is reported during the first 2 years after diagnosis, but conversion has been noted up to 15 years after diagnosis. Once conversion to multiple myeloma is complete, less than 10% of patients will survive 10 years

Novel Approach for Evaluation of Bacteroides fragilis Protective Role against Bartonella henselae Liver Damage in Immunocompromised Murine Model

Bartonella henselae is a gram-negative facultative intracellular bacterium and is the causative agent of cat-scratch disease. Our previous data have established that Bacteroides fragilis colonization is able to prevent B. henselae damages through the polysaccharide A (PSA) in an experimental murine model. In order to determine whether the PSA is essential for the protection against pathogenic effects of B. henselae in immunocompromised hosts, SCID mice were co-infected with B. fragilis wild type or its mutant B. fragilis 1PSA and the effects of infection on murine tissues have been observed by High-Frequency Ultrasound (HFUS), histopathological examination, and Transmission Electron Microscopy (TEM). For the first time, echostructure, hepatic lobes length, vascular alterations, and indirect signs of hepatic dysfunctions, routinely used as signs of disease in humans, have been analyzed in an immunocompromised murine model. Our findings showed echostructural alterations in all infected mice compared with the Phosphate Buffer Solution (PBS) control group; further, those infected with B. henselae and co-infected with B. henselae/B. fragilis 1PSA presented the major echostructural alterations. Half of the mice infected with B. henselae and all those co-infected with B. henselae/B. fragilis 1PSA have showed an altered hepatic echogenicity compared with the renal cortex. The echogenicity score of co-infected mice with B. henselae/B. fragilis 1PSA differed significantly compared with the PBS control group (p < 0.05). Moreover the inflammation score of the histopathological evaluation was fairly concordant with ultrasound findings. Ultrastructural analysis performed by TEM revealed no significant alterations in liver samples of SCID mice infected with B. fragilis wild type while those infected with B. fragilis 1PSA showed the presence of collagen around the main vessels compared with the PBS control group. The liver samples of mice infected with B. henselae showed macro-areas rich in collagen, stellate cells, and histiocytic cells. Interestingly, our data demonstrated that immunocompromised SCID mice infected with B. henselaeand co-infected with B. henselae/B. fragilis ΔPSA showed the most severe morpho-structural liver damage. In addition, these results suggests that the HFUS together with histopathological evaluation could be considered good imaging approach to evaluate hepatic alterations

Surprising autopsy diagnosis in unclear initial situation. A case of intravascular B cell lymphoma

Intravascular large B cell lymphoma (IVLBCL) is a rare extranodal non-Hodgkin lymphoma characterized by proliferation of malignant cells within the lumen of small vessels, with a predilection for the central nervous system and the skin [1]. IVLBCL clinical course is highly aggressive, clinical signs and symptoms are not specific and may consist in neurological deficits, fever of unknown origin, cutaneous lesions, lacking of a typical neuroimaging pattern [1]. For all these reasons the diagnosis is frequently missed and the exitus is frequent, therefore post-mortem evaluation is necessary to clarify the clinical history. We present a case of IVLBCL in a 62-year-old female with unusual symptomatology, mimicking a vascular multinfarctual cerebropathy; post-mortem autopsy was diriment to define the nature of the disease. Immu- nohistochemical analysis for anti-CD20 revealed the ubiquitary presence of malignant lymphoid B-cells into the vessels of all organs analyzed, allowing the definitive diag- nosis. Although the diagnostic procedure for such pathology is still a matter for fur- ther studies, adequate interpretation of neuro-imaging and morphological findings, as well as of systemic symptoms can provide a right diagnostic hypothesis, suggest- ing focused biopsy in vivo

Squamous cell carcinoma of the lower lip: FAS/FASL expression, lymphocyte subtypes and outcome.

Squamous cell carcinoma (SCC) of the lip is a relatively common malignancy of the head and neck region. Tumour thickness, grading and perineural invasion are significant prognostic indicators. However, there is still the need of new reliable biological markers able to predict the prognosis of the single cases with an unfavourable biological behaviour unpredictable by the classic clinical-pathological parameters. 32 cases of (SCC) of the lower lip were analysed for their clinicopathologic features, and immunohistochemical expression of Fas/FasL in neoplastic cells and in inflammatory infiltrate. Moreover the density and phenotype of tumour-infiltrating lymphocytes (TIL) were analysed. The results were related with the follow-up of the patients ranging from 2 to 6 years. The cases with over-expression of Fas/FasL in neoplastic cells and Fas+ in T cells preferentially showed a more aggressive clinical behaviour (p<0.01). Moreover we found an alteration of the normal expression of CD4 and CD8 lymphocyte types in ten cases. This data suggest that the Fas/FasL pathway is involved in the close relation between neoplastic cells and T cells and so in the biological behaviour of these tumours

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts

High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control

Transcription Factor EB Controls Metabolic Flexibility during Exercise

The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism