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The aim of this study was to investigate the effects of the lipid mediator Resolvin D1 in experimental keratitis. C57BL/6J mice were injected with lipopolysaccharide (2 µg/eye), and after 24 hours, the corneal damage was assessed. Clinical score was quantified, and corneal inflammatory biomarkers were detected by immunohistochemistry. A robust accumulation of sub‐epithelial macrophages and polymorphonuclear leucocytes, chemokine (C‐X‐C motif) ligand 1 (also known as keratinocyte‐derived chemokine), interleukin‐10 and promoters of apoptosis was also observed in lipopolysaccharide‐treated mice. Formyl peptide receptor 2 corneal expression was also assessed. The corneal stroma treated with lipopolysaccharide was characterized by presence of macrophages of M1‐like subtype and immature fibroblastic cells, marked with Ki67, not fully differentiated in fibroblasts. Indeed, the staining of the cornea with anti‐vimentin antibodies, a marker of differentiated myofibroblasts, was very faint. Resolvin D1 attenuated all the inflammatory parameters assessed in the present study, except for IL‐10. In conclusion, the data presented here seem to be consistent with the hypothesis that Resolvin D1 protected the cornea from the lipopolysaccharide‐induced keratitis by acting on several inflammatory components of this damage, pivoted by Formyl peptide receptor 2 (FPR2) activation and macrophages‐leucocytes activity.

Background: Microsatellite instability (MSI) is a predictive biomarker for immune checkpoint inhibitors. The main goal was to investigate the discordance between IHC and PCR/NGS for MSI testing in gastrointestinal cancers. Methods: Two series were analyzed through IHC for mismatch-repair-system proteins (MMRP) and PCR, with one series of 444 colorectal cancers (CRC) and the other of 176 gastric cancers (GC). All cases with discordant results between IHC and PCR were analyzed by NGS. IHC staining was evaluated as follows: proficient MMR (pMMR), with all MMR positive; deficient MMR (dMMR), with the loss of one heterodimer; and cases with the loss/patchy expression of one MMR (lo-paMMR). Cases with instability in at least two markers by PCR were MSI-high (MSI-H) and with instability in one marker, MSI-low (MSI-L). Cases without instability were evaluated as microsatellite-stable (MSS). Results: In the CRC cohort, 15 out of 444 cases were dMMR and 46 lo-paMMR. Among the 15 dMMR, 13 were MSI-H and 2 MSS. Among the 46 lo-paMMR, 13 were MSI-H and 33 were MSS. In the GC cohort, 13 out of 176 cases were dMMR and 6 cases lo-paMMR. Among the 13 dMMR, 12 were MSI-H and only 1 was MSS. All six lo-paMMR cases were MSS. All NGS results were in agreement with PCR. Conclusions: In clinical practice, MMR–IHC could be used as a screening test and additional molecular analysis is mandatory exclusively in cases carrying loss/patchy MMR-IHC.

Introduction: The mesenchymal-epithelial transition factor (c-MET) receptor is overexpressed in about 14–54% of invasive breast cancers, but its prognostic value in clinical practice is still unclear. Methods: In order to investigate the relationship between c-MET expression levels and prognosis, we retrospectively reviewed the clinical features and outcomes of 105 women with estrogen receptor positive HER2 negative (ER+/HER2-) resected breast cancer. We used the Kaplan Meier method to estimate Disease Free Survival (DFS) and Breast Cancer Specific Survival (BCSS) in the subgroups of patients with high (≥50%) and low (

This study aimed at investigating the SGLT2 expression in human cardiomyocytes. Human studies evaluating cardiomyocyte SGLT2s expression are limited. To better clarify this issue, SGLT2 protein expression was assessed in human hearts of diabetic and non-diabetic patients, and in AC16 human cardiomyocyte cell line. A prospective study with a follow-up of patients who underwent their first heart transplant (HTX) was performed. Explanted heart, basal (1 week after HTX), and final (48 weeks after HTX) endomyocardial biopsies (EMBs) from patients were evaluated for SGLT2 occurrence in cardiomyocyte with immunohistochemistry, immunofluorescence and SGLT2 quantization with both real-time reverse transcription-polymerase chain reaction and Western blot analysis. The immunofluorescence co-localization of SGLT2 in cardiomyocyte evidenced that an increased expression in the explanted heart from diabetic patients compared to non-diabetic (p&nbsp

Lipoma colónico; Cirugía Lipoma colònic; Cirurgia Colonic lipoma; Surgery Background: Colonic lipomas are rare and can sometimes cause intussusception. The aim of this review was to define the presentation and possible management for colocolic intussusception caused by colonic lipomas. Methods: A systematic search for patients with colocolic intussusception caused by colonic lipoma, including all available reports up to 2021. Epidemiological, clinical, laboratory, and instrumental data and details about the treatments performed were gathered. Results: Colocolic intussusception caused by lipoma is more frequent in women (57%), occurring between 40 and 70 years of age. Up to 83% of patients report abdominal pain, followed by constipation (18%), rectal bleeding (16%), and diarrhea (12%), with abdominal tenderness (37%), and distension in 16%, whereas 24% have a negative exploration. CT (72%) and colonoscopy (62%) are more commonly able to diagnose the entity. The most common location of intussusception is the transverse colon (28%). The surgical operation varies according to the site. The average dimensions of the lipoma are 59.81 × 47.84 × 38.9 mm3. Conclusions: A correct preoperative diagnosis of colonic lipoma causing intussusception might not be easy. Despite nonspecific clinical and laboratory presentation, cross-sectional imaging can help differential diagnosis. Surgical treatment depends on the localization. This research received no external funding.

Primary percutaneous coronary intervention (PPCI) is a pivotal treatment in ST-segment elevation myocardial infarction (STEMI) patients. However, in hyperglycemic-STEMI patients, the incidence of death is still significant. Here, the involvement of sirtuin 1 (SIRT1) and miR33 on the pro-inflammatory/pro-coagulable state of the coronary thrombus was investigated. Moreover, 1-year outcomes in hyperglycemic STEMI in patients subjected to thrombus aspiration before PPCI were evaluated. Results showed that hyperglycemic thrombi displayed higher size and increased miR33, reactive oxygen species, and pro-inflammatory/pro-coagulable markers. Conversely, the hyperglycemic thrombi showed a lower endothelial SIRT1 expression. Moreover, in vitro experiments on endothelial cells showed a causal effect of SIRT1 modulation on the pro-inflammatory/pro-coagulative state via hyperglycemia-induced miR33 expression. Finally, SIRT1 expression negatively correlated with STEMI outcomes. These observations demonstrate the involvement of the miR33/SIRT1 pathway in the increased pro-inflammatory and pro-coagulable state of coronary thrombi in hyperglycemic STEMI patients.

Background and purpose: pericoronary fat over-inflammation might lead to the development and destabilization of coronary plaque in patients with pre-diabetes (PDM). Notably, pericoronary fat could over-express the sodium-glucose cotransporter 2 (SGLT2) and leptin, along with decreased sirtuin 6 (SIRT6) expression in PDM vs. normoglycemic (NG) patients undergoing coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). However, in the current study, we evaluated inflammatory markers, SGLT2, SIRT6, and leptin levels in pericoronary fat and, subsequently, 12-month prognosis comparing PDM to NG subjected to CABG for AMI. In addition, we evaluated in PDM patients the effects of metformin therapy on SIRT6 expression, leptin, and SGLT2 levels, and assessed its beneficial effect on nitrotyrosine and inflammatory cytokine levels. Methods: we studied AMI patients referred for CABG, divided into PDM and NG-patients. PDM patients were divided into never-metformin users and metformin users. Finally, we evaluated major adverse cardiac events (MACE) at a 12-month follow-up. Results: the MACE was 9.1% in all PDM and 3% in NG patients (p &lt, 0.05). Metformin users presented a significantly lower MACE rate in PDM than never-metformin users (p &lt, 0.05). PDM showed higher inflammatory cytokines, 3-nitrotyrosine levels, SGLT2, and leptin content, and decreased SIRT6 protein levels in pericoronary fat compared to NG-patients (p &lt, 0.05). PDM never-metformin-users showed higher SGLT2 and leptin levels in pericoronary fat than current-metformin-users (p &lt, 0.05). Conclusions: metformin therapy might ameliorate cardiovascular outcomes by reducing inflammatory parameters, SGLT2, and leptin levels, and finally improving SIRT6 levels in AMI-PDM patients treated with CABG.

Objective We evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients. Methods Plaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up. Results Compared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P, Highlights • The identification of novel molecular targets of atherosclerosis progression is of utmost importance in diabetic patients. • The occurrence of SGLT2 receptors on the endothelial cells of atherosclerotic plaques may be an attractive therapeutic option for atherosclerosis in patients with diabetes. • SGLT2/SIRT6 represents an attractive option, given its crucial involvement in atherosclerosis progression. • The endothelial SGLT2 inhibition increases the endothelial expression of SIRT6, yielding an improved atherosclerotic plaque phenotype and 2-year outcome. • The impairment of the endothelial SGLT2/SIRT6 pathway worsens outcomes in atherosclerotic patients with diabetes; this may be a potential preventive target.

Backgrounds: Obese pre-diabetics over express cytokines that influence myocardial function via microRNAs (miRs) expression. Objectives: To evaluate inflammatory/oxidative stress, miRs’ expression and cardiovascular function in obese pre-diabetics assigned to metformin therapy vs. placebo vs. normo-glycemics at 12 months of follow-up. Materials and methods: Eighty-three obese patients after abdominoplastic surgery were divided in pre-diabetics (n 55), normo-glycemics (n 28), and assigned to hypocaloric diet. Pre-diabetics were assigned to metformin (n 23) or to placebo (n 22) plus hypocaloric diet. Results: Obese pre-diabetics in metformin vs. placebo, and obese pre-diabetics with placebo vs. normoglycemics, had significant differences about IMT, MPI, and LVM (p < 0.05). Obese pre-diabetics in metformin vs. placebo showed significant reduction in serum miR-195 and miR-27 (p < 0.05). Obese pre-diabetics in metformin vs. normoglycemics showed higher expression of serum miR-195 and miR-27 (p < 0.05). Finally, we found inverse relation between IMT and insulin, HOMA-IR, miR-195, miR-27; between LVEF and Insulin, HOMA-IR, miR-195 and miR-27. We found inverse correlation between LVM and sirtuin-1, Insulin, HOMA-IR, miR-195 and miR-27, and direct correlation with interleukin-6. MPI inversely linked to miR-195 and miR-27. Conclusions: In obese pre-diabetics’, metformin significantly reduces inflammation/oxidative stress, and miR-195 and miR-27, with reduction in LVM, IMT.

Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N-palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells, (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines, (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas, (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI), (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation.

Background and Purpose: Diabetic retinopathy, a secondary complication of diabetes mellitus, can lead to irreversible vision loss. Currently, no treatment is approved for early phases of diabetic retinopathy. Modifications of the expression pattern of miRNAs could be involved in the early retinal damage of diabetic subjects. Therefore, we aimed at identification of dysregulated miRNAs–mRNA interactions that might be biomarkers and pharmacological targets for diagnosis and treatment of early diabetic retinopathy. Methods: A focused set of miRNAs was predicted through a bioinformatic analysis accessing to Gene Expression Omnibus dataset and enrichment of information approach (GENEMANIA-Cytoscape). Identification of miRNAs–mRNA interactions was carried out with miRNET analysis. Diabetes was induced in C57BL6J mice by streptozotocin and samples analysed at 5 and 10weeks after diabetes induction. Retinal ultrastructure of diabetic mice was analysed through electron microscopy. We used Real-time PCR, western blot analysis, elisa, and immunohistochemistry to study expression of miRNAs and possible targets of dysregulated miRNAs. Key Results: We found that miR-20a-5p, miR-20a-3p, miR-20b, miR-106a-5p, miR-27a-5p, miR-27b-3p, miR-206-3p, and miR-381-3p were dysregulated in the retina and serum of diabetic mice. VEGF, brain-derived neurotrophic factor (BDNF), PPAR-α, and cAMP response element-binding protein 1 (CREB1) are targets of dysregulated miRNAs, which then modulated protein expression in diabetic retina. We found structural modifications in retinas from diabetic mice. Conclusions and Implications: Serum and retina of diabetic mice express eight dysregulated miRNAs, which modified the expression of VEGF, BDNF, PPAR-α, and CREB1, before vasculopathy in diabetic retinas.

Objectives: In obese patients the superficial adipose tissue expresses cytokines, and sirtuins, that may affect myocardial function. In this study, we investigated the effect of metformin therapy added to a hypocaloric diet on the inflammatory pattern and cardiac performance (MPI) in obese patients with pre-diabetic condition. Materials and Methods: Fifty-eight obese patients that were enrolled for abdominoplastic surgery were divided into patients with pre-diabetic condition (n 40) and normo-glycemic patients (n18). Patients with pre-diabetic condition were randomly assigned to metformin therapy added to a hypocaloric diet (group 1, n 20) or to a hypocaloric diet therapy alone (group 2, n20). Patients with normo-glycemic condition were assigned to a hypocaloric diet therapy. Results: During enrollment, obese patients with a pre-diabetic condition (group 1 and 2) presented higher glucose values, lower values of insulin, and higher values of the homeostasis model for the assessment of insulin resistance (HOMA-IR) than obese patients with normo-glycemic condition(group 3). In addition, they had higher values of C Reactive protein (CRP), interleukin 6 (IL6), and lower values of sirtuin 1(SIRT1). In the 12th month of the follow-up, metformin therapy induced in patients with pre-diabetic condition (group 1) a significant reduction of glucose values, HOMA-IR, and inflammatory markers such as CRP (1.04 ± 0.48 vs. 0.49 ± 0.02 mmol/L, p < 0.05), IL6 (4.22 ± 0.45 vs. 3.33 ± 0.34 pg/ml, p < 0.05), TNFa (6.95 ± 0.59 vs. 5.15 ± 0.44 pg/ml, p < 0.05), and Nitrotyrosine (5,214 ± 0,702 vs. 2,151 ± 0,351 nmol/l, p < 0.05). This was associated with a significant reduction of Intima-media thickness (1.01 ± 0.15 vs. 0.86 ± 0.15 mm, p < 0.05), Septum (14 ± 2.5 vs. 10.5 ± 2 mm, p < 0.05), Posterior wall (11 ± 1.5 vs. 8 ± 1 mm, p < 0.05), LV mass (192.5 ± 49.5 vs. 133.2 ± 37.6 g, p < 0.05) and of MPI (0.58 ± 0.03 vs. 0.38 ± 0.02, p < 0.05). At 12 months of follow-up, group 2 experienced only a reduction of cholesterol (4.15 ± 0.94 vs. 4.51 ± 0.88 mmol/L, p < 0.05) and triglycerides (1.71 ± 1.18 vs. 1.83 ± 0.54 mmol/L, p < 0.05). At 12 months of follow-up, group 3 experienced a significant reduction of inflammatory markers, and also of echographic parameters, associated with amelioration of myocardial performance. To date, IL6 expression was related to higher values of left ventricle mass (R-value 0.272, p-value 0.039), and to higher IMT (R-value 0.272, p-value 0.039), such as those observed for CRP (R-value 0.308, p-value 0.021), for glucose blood values (R-value 0.449, p-value 0.001), and for HOMA-IR (R-value 0.366, p-value 0.005). An inverse correlation was found between subcutaneous fat expression of SIRT1 and myocardial performance index (R-value-0.236, p-value 0.002). Conclusion: In obese patients with pre-diabetic condition a metformin therapy may reduce inflammation and oxidative stress, and this may be associated with the amelioration of the cardiac performance. Objectives: In obese patients the superficial adipose tissue expresses cytokines, and sirtuins, that may affect myocardial function. In this study, we investigated the effect of metformin therapy added to a hypocaloric diet on the inflammatory pattern and cardiac performance (MPI) in obese patients with pre-diabetic condition. Materials and Methods: Fifty-eight obese patients that were enrolled for abdominoplastic surgery were divided into patients with pre-diabetic condition (n 40) and normo-glycemic patients (n18). Patients with pre-diabetic condition were randomly assigned to metformin therapy added to a hypocaloric diet (group 1, n 20) or to a hypocaloric diet therapy alone (group 2, n20). Patients with normo-glycemic condition were assigned to a hypocaloric diet therapy. Results: During enrollment, obese patients with a pre-diabetic condition (group 1 and 2) presented higher glucose values, lower values of insulin, and higher values of the homeostasis model for the assessment of insulin resistance (HOMA-IR) than obese patients with normo-glycemic condition(group 3). In addition, they had higher values of C Reactive protein (CRP), interleukin 6 (IL6), and lower values of sirtuin 1(SIRT1). In the 12th month of the follow-up, metformin therapy induced in patients with pre-diabetic condition (group 1) a significant reduction of glucose values, HOMA-IR, and inflammatory markers such as CRP (1.04 ± 0.48 vs. 0.49 ± 0.02 mmol/L, p < 0.05), IL6 (4.22 ± 0.45 vs. 3.33 ± 0.34 pg/ml, p < 0.05), TNFa (6.95 ± 0.59 vs. 5.15 ± 0.44 pg/ml, p < 0.05), and Nitrotyrosine (5,214 ± 0,702 vs. 2,151 ± 0,351 nmol/l, p < 0.05). This was associated with a significant reduction of Intima-media thickness (1.01 ± 0.15 vs. 0.86 ± 0.15 mm, p < 0.05), Septum (14 ± 2.5 vs. 10.5 ± 2 mm, p < 0.05), Posterior wall (11 ± 1.5 vs. 8 ± 1 mm, p < 0.05), LV mass (192.5 ± 49.5 vs. 133.2 ± 37.6 g, p < 0.05) and of MPI (0.58 ± 0.03 vs. 0.38 ± 0.02, p < 0.05). At 12 months of follow-up, group 2 experienced only a reduction of cholesterol (4.15 ± 0.94 vs. 4.51 ± 0.88 mmol/L, p < 0.05) and triglycerides (1.71 ± 1.18 vs. 1.83 ± 0.54 mmol/L, p < 0.05). At 12 months of follow-up, group 3 experienced a significant reduction of inflammatory markers, and also of echographic parameters, associated with amelioration of myocardial performance. To date, IL6 expression was related to higher values of left ventricle mass (R-value 0.272, p-value 0.039), and to higher IMT (R-value 0.272, p-value 0.039), such as those observed for CRP (R-value 0.308, p-value 0.021), for glucose blood values (R-value 0.449, p-value 0.001), and for HOMA-IR (R-value 0.366, p-value 0.005). An inverse correlation was found between subcutaneous fat expression of SIRT1 and myocardial performance index (R-value-0.236, p-value 0.002). Conclusion: In obese patients with pre-diabetic condition a metformin therapy may reduce inflammation and oxidative stress, and this may be associated with the amelioration of the cardiac performance.

Background: The rat model of streptozotocin (STZ)-induced pancreatic damage was used to examine whether a systemic oxygen/ozone mixture could be beneficial for the pancreas by reducing the machinery of the local detrimental mediators released by STZ. Results: The results showed that oxygen/ozone administration (150 µg/Kg i.p.) for ten days in STZ rats increased the endogenous glutathione-s-transferase (GST) enzyme and nuclear factor-erythroid 2-related factor 2 (Nrf2) into the pancreatic tissue, together with reduction of 4-hydroxynonenal (4-HNE) and PARP-1 compared to STZ rats receiving O₂ only. Interestingly, these changes resulted in higher levels of serum insulin and leptin, and pancreatic glucagon immunostaining. Consequently, glucose metabolism improved as evidenced by the monitoring of glycemia throughout. Conclusions: This study provides evidence that systemic administration of oxygen/ozone reduces the machinery of detrimental mediators released by STZ into the pancreas with less local damage and better functionality.

Fibrous histiocytomas are uncommon mesenchymal tumours of the soft tissue in the head and neck region. We report two cases that occurred in the oral cavity, one of a benign fibrous histiocytoma (BFH) and another of an angiomatoid variant of fibrous histiocytoma (AFH). BFH is a benign neoplasm composed of cells with fibroblastic and histiocytic characteristics, while AFH is considered as a distinct type of fibrous histiocytoma with an intermediate malignancy grade that combines features of both fibrohistiocytic and vascular neoplasm. We describe the clinicopathological and histological characteristics of these lesions to clarify and facilitate their diagnosis. In the BFH case, the surgical specimen had many histiocytes positive for lysozime, whereas the AFH cells showed positivity for endothelial cell marker (anti-CD34 antibody). In both cases the tumours were positive for fibronectin and negative for S100 and SMA. Ki-67. Immunohistochemistry was performed in all cases to reveal the different mitotic activity between AFH and BFH tumour cells. Finally, differential diagnoses and therapeutic treatments are discussed.

Aim: This study investigated whether telmisartan, a selective angiotensin type 1 (AT1) receptor antagonist and gamma peroxisome proliferator-activated receptor (PPAR-γ) partial agonist, reduces myocardial ischaemia/reperfusion (I/R) injury in an experimental model of metabolic syndrome. Methods: Zucker Diabetic Fatty (ZDF) rats were treated for 3 weeks with telmisartan at doses of 2, 7 and 12 mg/kg/day. After treatment, rats were subjected to a 25-min occlusion of the left descending coronary artery followed by 2-h reperfusion (I/R). Results: Telmisartan reduced the extension of the infarct size in a dose-dependent fashion and decreased the levels of plasma troponin I, a specific marker of myocardial damage. Telmisartan also caused a dose-dependent increase in adiponectin both in plasma and cardiac tissue of infarcted ZDF rats. These levels were minimally increased (p < 0.05 vs. vehicle) by telmisartan 7 mg/kg/day and reached the maximum values with the highest dose of 12 mg/kg/day (p < 0.01 vs. vehicle). In contrast, within the infarcted tissue telmisartan decreased the expression of markers of inflammation such as the transcription factor NF-κB, the toll-like receptors TLR2 and TLR4 as well as TNF-α cytokine. Nitrosative stress was maximal in vehicle-treated infarcted hearts as evidenced by increased expression of iNOS, which was almost abolished after treatement with telmisartan. Conclusions: Treatment of ZDF rats for 3 weeks with telmisartan, a dual angiotensin II receptor antagonist and partial PPAR-γ receptor agonist, resulted in a significant reduction of myocardial damage induced by I/R and was assocciated with increased adiponectin and a decrease in inflammatory markers.

Here, we have studied the effects of a carbon monoxide-releasing molecule (CORM-3, tricarbonylchloro(glycinato)ruthenium(II)) on acute myocardial ischemia/reperfusion (I/R) injury in hyperglycaemic streptozotocin-treated rats (STZ rats). Occlusion of the left descending coronary artery for 25 min followed by a 2-h reperfusion in STZ-induced hyperglycaemic rats was used as the model. CORM-3 and its inactive counterpart (iCORM-3) were administered 1 h prior to ischemia. The parameters measured included myocardial infarct size (IS) and a selection of inflammatory, oxidative markers and endothelial progenitor cells (CD34+ and CD117/c-kit+). In STZ-induced hyperglycaemic rats, occlusion of the left descending coronary artery caused injury of the myocardial tissue with an IS of ~70%, expressed as fraction of the area at risk. Given intraperitoneally 1 h prior to ischemia, CORM-3 (2–8 mg/kg) afforded significant dose-dependent cardio-protection. Specifically, pre-treatment with CORM-3 reduced infarct size by 14 ± 0.6%, 34 ± 1% and 53 ± 1.6% for doses of 2, 4 and 8 mg/kg, respectively. A negative control (iCORM-3) failed to prevent the cardiac damage induced by I/R. CORM-3 pre-treatment augmented cardiac heme oxygenase-1 (HO-1) protein levels and was associated with an increased number of CD34+- and CD117/c-kit+-positive immunostaining. Modulation of these markers was associated with augmented cardiac eNOS expression and levels of the cytokines TNF-α and IL-1 beta. CORM-3 afforded significant cardio-protection against acute myocardial infarction in STZ-induced hyperglycaemic rats through liberation of small amounts of CO. Of interest, CORM-3 promoted recruitment of the endogenous endothelial progenitor cells within the myocardium, possibly through modulation of cardiac HO-1 and eNOS expression and/or function.

CONTEXT: A strong association between subclinical hypothyroidism (SCH) and atherosclerotic diseases, independent of the traditional risk factors, was noted. OBJECTIVE: The objective of the study was to evaluate the association between SCH and the inflammatory potential of atherosclerotic plaques as well as the role of L-T(4) replacement therapy (LTR) on regulation of plaque inflammation. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We examined the differences in macrophage content, proinflammatory cytokine infiltration, and oxidative stress between asymptomatic carotid plaques of patients with and without SCH and LTR. SETTING AND PARTICIPANTS: Plaques were obtained from 23 SCH patients with LTR (treated), 34 untreated SCH patients, and 30 control patients without SCH enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen (HLA)-DR(+) cells, nuclear factor-κB (NF-κB), inhibitory-κBβ (IκBβ), TNF-α, nitrotyrosine, matrix metalloproteinase-9 (MMP-9), and collagen content (immunohistochemistry and ELISA). RESULTS: Compared with control plaques, SCH plaques had more macrophages, T lymphocytes, and HLA-DR(+) cells, TNF-α, NF-κB, markers of oxidative stress (nitrotyrosine and O(2-) production), and MMP-9 (P < 0.01, for all), along with a lesser collagen content and IκBβ levels (P < 0.001). Compared with plaques from treated patients, plaques from untreated patients had more macrophages, T lymphocytes, HLA-DR(+) cells, TNF-α, NF-κB (P < 0.001), nitrotyrosine, O(2-) production, and MMP-9 (P < 0.01, for all), along with a lesser collagen content and IκBβ levels (P

Objectives. We analyzed the molecular mechanisms evoked by tight glycemic control during post-infarction remodeling in human hearts. Background. The molecular mechanisms by which tight glycemic control improves heart remodeling during acute myocardial infarction (AMI) are still largely unknown. Methods. Eighty-eight patients with first AMI undergoing coronary bypass surgery were studied: 38 normoglycemic patients served as the control group; hyperglycemic patients (glucose =140 mg/dl) were randomized to intensive glycemic control (IGC) (n = 25; glucose 80 to 140 mg/dl) or conventional glycemic control (CGC) (n = 25; glucose 180 to 200 mg/dl) for almost 3 days before surgery, with insulin infusion followed by subcutaneous insulin treatment. Echocardiographic parameters were investigated at admission and after treatment period. During surgery, oxidative stress (nitrotyrosine, superoxide anion [O2 –] production, inducible nitric oxide synthase [iNOS]),inflammation (nuclear factor kappa B [NF_B], tumor necrosis factor [TNF]-a, and apoptosis (caspase-3) were analyzed in biopsy specimens taken from the peri-infarcted area. Results. Compared with normoglycemic patients, hyperglycemic patients had higher myocardial performance index (MPI) (p < 0.05), reduced ejection fraction (p 0.05), more nitrotyrosine, iNOS, and O2 _ production, more macrophages, T-lymphocytes, and HLA-DR (Dako, Milan, Italy) cells, and more NF_B-activity, TNF-a, and caspase-3 levels (p < 0.01) in peri-infarcted specimens. After the treatment period, plasma glucose reduction was greater in the IGC than in the CGC group (p < 0.001). Compared with IGC patients, CGC patients had higher MPI (p _0.02), had lower ejection fraction (p < 0.05), and had more markers of oxidative stress, more inflammation and apoptosis (p < 0.01) in peri-infarcted specimens. Conclusions. Tight glycemic control, by reducing oxidative stress and inflammation, might reduce apoptosis in peri-infarcted areas and remodeling in AMI patients.

BACKGROUND The role of the ubiquitin-proteasome system in the vascular senescence and atherosclerotic progression of elderly patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic elderly and adult patients. METHODS Plaques were obtained from 28 elderly and 18 adult patients undergoing carotid endarterectomy. Plaques were analyzed for ubiquitin levels, proteasome 20S activity, p16 and p53, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Serial sections were incubated with specific antibodies anti-human leukocyte antigen (HLA)-DR, anti CD68 and anti-CD3. RESULTS Compared to plaques obtained from adult patients, plaques of elderly patients had more ubiquitin levels (257.4 +/- 118.9 ng/mg vs 110 +/- 14.4 ng/mg, p

Esophageal squamous papilloma (ESP) is a benign epithelial lesion. ESP is extremely rare and it has been described in few cases in literature. The etiology of ESP may be associated to chronic mucosal irritation and HPV infection. It is usually asymptomatic and mostly discovered as an incidental finding during upper gastrointestinal endoscopy. It is considered a benign neoplasia but recent reports have stressed the potential malignant evolution of these lesions. A 53 year old caucasian woman presented with a four years history of disphagia not responsive to medical therapy. At upper endoscopy, esophageal mucosa appeared hyperemic and completely covered by numerous (>100) sessile peduncolate papules. Biopsies demostrating atypical epithelial proliferation confirmed the diagnosis of esophageal squamal papillomatosis with low grade and focal high grade dysplasia; in situ hybridization studies for HPV were perfomed and it was positive for the type 16. We report a case of diffuse esophageal papillomatosis with histologic and microbiologic findings of genotype 16 HPV and Lichen Planus infection successfully treated with an Ivor Lewis Esophagectomy and a second look endoscopy by radiofrequency ablation.

Whether morning blood pressure surge influences the molecular mechanisms of plaque progression toward instability is not known. Recently, we have demonstrated enhanced activity of the ubiquitin–proteasome system in human plaques and evidenced that it is associated with inflammatory-induced plaque rupture. We evaluated the inflammatory infiltration and ubiquitin–proteasome activity in asymptomatic carotid plaques of hypertensive patients with different patterns of morning blood pressure surge. Plaques were obtained from 32 hypertensive patients without morning blood pressure surge and 28 with morning blood pressure surge enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T-lymphocytes, human leukocyte antigen–DR+cells, ubiquitin–proteasome activity, nuclear factor-κB, inhibitor kB-β, tumor necrosis factor-α, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques obtained from hypertensive patients without morning blood pressure surge, plaques from with morning blood pressure surge had more macrophages, T-lymphocytes, human leukocyte antigen–DR+cells ( P P P P

A mouse model of neuropathic pain consisting of chronic constriction injury (CCI) of the sciatic nerve was used to examine the involvement of reactive oxygen species (ROS) in early spinal cord pro-apoptotic gene over-expression during the development of neuropathic pain. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), and caspase-9 in the dorsal horn spinal cord 3 days after chronic constriction injury of sciatic nerve. Consistent with biomolecular data, a marked increase in TUNEL-positive and caspase-3 active form was observed by 3 days CCI. Administration of phenyl-N-tert-butylnitrone (PBN), a potent ROS scavenger, reduced the development of thermal hyperalgesia and mechanical allodynia at 1 and 3 days post-CCI, and decreased the mRNA levels of bax, apaf-1, and caspase-9. PBN also reduced apoptotic and active Caspase-3 positive profiles in the superficial laminae (I-III) of the spinal cord. This study provides evidence that PBN inhibits over-expression of pro-apoptotic genes and neural apoptosis in the spinal cord dorsal horn induced by early-CCI of the sciatic nerve. These findings suggest that ROS regulate expression of some apoptotic genes which might play a role in the onset of neuropathic pain.

Increased Activity of the Ubiquitin-Proteasome System in Patients With Symptomatic Carotid Disease Is Associated With Enhanced Inflammation and May Destabilize the Atherosclerotic Plaque: Effects o...

The study of cystic cavities and collagen fibers fragmentation is useful to for a better knowledge of pathogenesis and surgical therapy of medial ascending aortic degeneration. Thus, the aim of this study was to describe by scanning electron microscopy the surfaces and shape of the cysts, measure their area, and identify microcystic spaces related to this degenerative disease. Scanning electron microscopy analysis was performed in 16 out of 36 patients who underwent surgery for ascending aorta dilatation with associated aortic valve disease. The aortic medial wall showed a cribrose appearance at low magnification (x50-100) and the intima was effuse. At high magnification (x500-2000), small cavities (clefts) lined by normal or fragmented elastic fibers and large cavities (pseudocystes) with anfractuous borders lined by fragmented elastic fibers and smooth muscle cells were observed. Furthermore, in the outer media wall microvessels lined by endothelium were also observed. These changes were lacking or less pronounced in normal aorta. SEM allows one to better identify the pathological cavities and to differentiate them from microvessels. These pathological cavities are more numerous and larger in the convexity than in the concavity of the aorta in according to our previous morphological and morphometric findings in asymmetrical aorta dilatation.

This study investigated the protective effects of intravitreal Resolvin D1 (RvD1) against LPS-induced rat endotoxic uveitis (EIU). RvD1 was administered into the right eye at a single injection of 5 μL volume containing 10–100–1000 ng/kg RvD1 1 h post-LPS injection (200 μg,Salmonella minnesota) into thefootpad of Sprague-Dawley rats. 24 h later, the eye was enucleated and examined for clinical, biochemical, and immunohistochemical evaluations. RvD1 significantly and dose-dependently decreased the clinical score attributed to EIU, starting from the dose of 10 ng/kg and further decreased by 100 and 1000 ng/kg. These effects were accompanied by changes in four important determinants of the immune-inflammatory response within the eye: (i) the B and T lymphocytes, (ii) the miRNAs pattern, (iii) the ubiquitin-proteasome system (UPS), and (iv) the M1/M2 macrophage phenotype. LPS+RvD1 treated rats showed reduced presence of B and T lymphocytes and upregulation of miR-200c-3p, miR 203a-3p, miR 29b-3p, and miR 21-5p into the eye compared to the LPS alone. This was paralleled by decreases of the ubiquitin, 20S and 26S proteasome subunits, reduced presence of macrophage M1, and increased presence of macrophage M2 in the ocular tissues. Accordingly, the levels of the cytokine TNF-α, the chemokines MIP1-αand NF-κB were reduced.

Objective: To investigate whether and how the severity of medial degeneration (MD) lesions varies along the circumference of the dilated intrapericardial aorta. Methods: Two groups of aortic wall specimens, respectively harvested 1 cm distal to the non-coronary (NC) sinus (right postero-lateral wall) and to the right coronary sinus (anterior wall) in 22 patients undergoing surgery for dilatation of the intrapericardial aorta associated with aortic valve disease, were separately sent for pathology, morphometry and ultrastructural examination. MD lesions found at histology were classified into three degrees of severity. MD mean degree and morphometric findings in postero-lateral (‘NC’) and anterior (‘coronary’) specimens were compared by paired t-test. Correlation between degree of aortic dilatation at echocardiography and severity of MD was assessed separately for each of the two groups of specimens. After the preliminary results of the morphological study, we decided to send the specimens for biochemical investigation of protein electrophoretic patterns. This was performed in the last seven patients of this series. Results: At histology, MD was found in all cases. A higher mean MD degree was found in the NC group (2.59 ^ 0.50 versus 1.59 ^ 0.67 in the coronary group; P , 0:001). At morphometry, normal smooth muscle cells in the NC specimens were significantly reduced ðP ¼ 0:012Þ and the length ðP ¼ 0:011Þ and number ðP ¼ 0:015Þ of elastic fibres reduced and increased, respectively. Correlation between aortic ratio and MD degree was significant in the NC specimens ðP , 0:001Þ, not in the coronary ones ðP ¼ 0:227Þ. Quantitative differences between coronary and NC proteins from the same patient and between coronary proteins from different patients were found at electrophoresis. However, at this stage of the study, the sample was too small to allow for the identification of proteins involved in those differences. Conclusions: MD lesions in dilated intrapericardial aorta are more severe in the right postero-lateral wall area, likely due to haemodynamic stress asymmetry. q 2002 Elsevier Science B.V. All rights reserved.

4-Methylpyrazole (4-MP), a specific inhibitor ofalcohol dehydrogenase, exerts gastroprotection ofunusually long duration in rats. We tested thehypothesis that pretreatment with 4-MP might protect the human gastric mucosa against alcohol-inducedacute injury. Fourteen healthy volunteers receivedpretreatment with either 4-MP, 15 mg/kg body weightdissolved in 50 ml of orange juice, or placebo and 2 hr later 100 ml of 40% ethanol. The endoscopicappearance of the gastric mucosa was evaluated andscored (scale 0-5) and mucosal biopsies were obtainedjust before pretreatment and 30 min after ethanol for histologic examination and prostaglandinE2 measurement. In the 4-MP group the meanendoscopic injury score was significantly lower thanthat in placebo group, in both the body and the antrum.Histologically, 4-MP significantly reduced disruption ofsurface epithelium and completely prevented the deephemorrhagic mucosal lesions. In the 4-MP group nochanges in gastric mucosal PGE2 levels weredetected. In rats, 4-MP did not inhibit gastric acid output,whereas it markedly increased the adherent gastric mucusevaluated by the alcian blue recovery method. When lipidperoxidation was induced by carbon tetrachloride in hepatic microsomes, 4-MP caused significantinhibition of malondialdehyde generation. We concludethat 4-MP provides significant protection of the humanstomach against alcohol-induced acute mucosal injury. 4-MP, besides inhibiting the conversionof alcohol to acetaldehyde, might protect the gastricmucosa by increasing adherent gastric mucus and byscavenging free radicals.

The study investigated the effects of the aldose reductase (AR) inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy) benzofuroxane (herein referred to as BF-5m) on the biochemical and tissue alterations induced by endotoxic uveitis in rats. BF-5m has been administered directly into the vitreous, in order to assess the expression and levels of (i) inflammatory markers such as the ocular ubiquitin-proteasome system, NF-κB, TNF-α, and MCP-1; (ii) prooxidant and antioxidant markers such as nitrotyrosine, manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPX); (iii) apoptotic/antiapoptotic factors caspases and Bcl-xl; (iv) markers of endothelial progenitor cells (EPCs) recruitment such as CD34 and CD117. 5 μL of BF-5m (0.01; 0.05; and 0.1 μM) into the right eye decreased in a dose-dependent manner the LPS-induced inflammation of the eye, reporting a clinical score 1. It reduced the ocular levels of ubiquitin, 20S and 26S proteasome subunits, NF-κB subunits, TNF-α, MCP-1, and nitrotyrosine. BF-5m ameliorated LPS-induced decrease in levels of MnSOD and GPX. Antiapoptotic effects were seen from BF-5m by monitoring the expression of Bcl-xl, an antiapoptotic protein. Similarly, BF-5m increased recruitment of the EPCs within the eye, as evidenced by CD34 and CD117 antibodies.

This study investigated the involvement of proteasome and macrophages M2 in the protection afforded by telmisartan against the acute myocardial infarction in Zucker diabetic fatty (ZDF) rats with metabolic syndrome. ZDF rats were treated for three weeks with telmisartan at doses of 7 and 12 mg/kg/day. After treatment, rats were subjected to a 25 min occlusion of the left descending coronary artery followed by 2 h reperfusion (I/R). At the end of the I/R period, biochemical, immunohistochemical, and echocardiographic evaluations were done. Telmisartan treatment (7 mg/kg and 12 mg/kg) reduced the myocardial infarct size, the expression of proteasome subunits 20S and 26S, and the protein ubiquitin within the heart. The compound has led to an increased M2 macrophage phenotype within the cardiac specimens and a modification of the cardiac cytokine and chemokine profile. This was functionally translated in improved cardiac performance as evidenced by echography after 2 h reperfusion. 7 mg/kg/day telmisartan was sufficient to improve the left ventricular ejection fraction LVEF of the rat heart recorded after I/R (e.g., vehicle 38 ± 2.2%; telmisartan 54 ± 2.7%) and was sufficient to improve the diastolic function and the myocardial performance index up to values of 0.6 ± 0.01 measured after I/R.

The pathophysiology of chronic diabetic ulcers is complex and still incompletely understood, both micro- and macroangiopathy strongly contribute to the development and delayed healing of diabetic wounds, through an impaired tissue feeding and response to ischemia. With adequate treatment, some ulcers may last only weeks; however, many ulcers are difficult to treat and may last months, in certain cases years; 19–35% of ulcers are reported as nonhealing. As no efficient therapy is available, it is a high priority to develop new strategies for treatment of this devastating complication. Because experimental and pathological studies suggest that incretin hormone glucagon-like peptide-1 may improves VEGF generation and promote the upregulation of HIF-1αthrough a reduction of oxidative stress, the study evaluated the effect of the augmentation of GLP-1, by inhibitors of the dipeptidyl peptidase-4, such as vildagliptin, on angiogenesis process and wound healing in diabetic chronic ulcers. Although elucidation of the pathophysiologic importance of these aspects awaits further confirmations, the present study evidences an additional aspect of how DPP-4 inhibition might contribute to improved ulcer outcome.

In the recent literature there has been an increased interest in the effects of particulate matter on the respiratory tract. The objective of this study was to use an in vitro model of type II lung epithelium (A549) to evaluate the cell ability to take up sub-micron PM(1.0) particles (PM(1.0)), Parietaria officinalis (ALL), and PM(1.0) + ALL together. Morphological analysis performed by Transmission Electron Microscope (TEM) showed that PM and ALL interacted with the cell surface, then penetrating into the cytoplasm. Each single treatment was able to point out a specific change in the morphology. The cells treated appear healthy and not apoptotic. The main effect was the increase of: multilamellar bodies, lysosomal enzymes, microvilli, and presence of vesicle/vacuoles containing particles. These observations demonstrate morphological and functional alterations related to the PM(1.0) and P. officinalis and confirm the induction of the inflammatory response in lung cells exposed to the inhalable particles.

Asthma is currently defined as a chronic inflammatory disease of the airway. Several evidence indicate that vehicle emissions in cities is correlated with the allergic respiratory diseases. In the present study, we evaluated in the A549 cells the production and release of IL-4, IL-5 and IL-13 after treatment with sub-micron PM 1.0 particles (PM 1.0 ), Parietaria officinalis (ALL), and PM 1.0 + ALL together. Our data demonstrated that PM 1.0 + ALL together exhibited the greatest capacity to induce A549 cells to enhance the expression of IL-4 and IL-5 compared with the only PM 1.0 or ALL treatment. Interestingly, IL-13 that is necessary for allergen-induced airway hyper responsiveness, is increased in cells treated with PM 1.0 + ALL together, but is higher expressed when the cells are treated only with the allergen. Our data support the hypothesis that the urban environment damage the acinar lung units and activates cells of the immune system.

We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

The purpose of this study is to investigate whether an oxygen/ozone (O(2)/O(3)) mixture protects the heart from acute myocardial infarction through local involvement of endothelial nitric oxide synthase (eNOS) and endothelial progenitor cells (EPCs). Male Sprague-Dawley rats were subject to 25-min occlusion and 2-h reperfusion of the left descending coronary artery. O(2)/O(3) mixture was insufflated i.p. 30 min prior to ischemia/reperfusion (I/R) procedure at doses of 100, 150, and 300 microg/kg. Myocardial infarct size (IS) measurement and myocardial immunohistochemistry for EPCs were done. For these latter cells, immunoreactivities for CD34, and CD117/c-kit were assessed within the infarcted tissue. Moreover, cardiac eNOS was monitored. I/R in rats treated with O(2) produced an IS as a percentage of the area at risk (IS/AR) equal to 51 +/- 5%. I/R in rats treated with the O(2)/O(3) mixture showed reduced IS (for example, IS/AR for 150 microg/kg O(2)/O(3) was 35 +/- 2.1%; P0.01 vs. O(2)). The O(2)/O(3) cardio-protection was paralleled by an increased number of immunopositive particles per area for CD34 and CD117/c-kit. The increase of these markers was associated with an increase of cardiac eNOS expression as assayed by immunohistochemistry. Interestingly, N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO), a selective eNOS activity inhibitor (30 mg/kg s.c.), prior to O(2)/O(3) and I/R almost abolished the cardio-protection exerted by the O(2)/O(3) mixture. L-NIO also abolished the increase in immunostaining for CD-34 and CD117/c-kit as compared with the rats receiving O(2)/O(3) and I/R only. O(2)/O(3) mixture protects the heart from acute myocardial infarction through local increase of eNOS expression/activity and consequent EPCs recruitment.

The role of surgically removing subcutaneous fat by abdominoplasty on circulating inflammatory markers and myocardial dysfunction, evaluated by myocardial performance index (MPI), were investigated. Twenty volunteers submitted to the abdominoplasty (abdominoplasty group), and other 28 women treated by hypocaloric diet (diet group) were evaluated. Echocardiographic parameters of MPI, circulating levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, were performed at baseline and 2 months later. Compared with nonobese women, obese women had increased concentrations of TNF-alpha (P < 0.01), IL-6 (P < 0.01), and higher MPI (P < 0.02), indicating ventricular dysfunction. Subcutaneous fat concentrations of TNF-alpha and IL-6 were related to MPI impairment. After 60 days, waist-to hip ratio was significantly reduced in the abdominoplasty group. Anthropometric changes were accompanied by a significant decline in plasma concentrations of TNF-alpha and IL-6 levels as well as by significant improvements of MPI in abdominoplasty group compared with diet group. Abdominoplasty may represent a safe method for ameliorating cardiac function in obese women.

Background: Because the ubiquitin-proteasome pathway (UPS) is required for activation of nuclear factor kappa beta (NFkB), a transcription factor that regulates inflammatory genes, we evaluated the UPS activity, NFkB activation, and tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, in ischemic specimens of diabetic myocardium and relate them to the glycemic control (HbA1c), oxidative stress (nitrotyrosine, a modified amino acid produced by reactive O2), and cardiac outcome (echocardiographic parameters). Moreover, the role of UPS, NFkB, and TNF-alpha in the cardiac tissue injury of acute ischemia/reperfusion (I/R) was evaluated in streptozotocin (STZ)-hyperglycemic rats. Finally, this study aimed to elucidate whether an intervention on UPS with bortezomib, an inhibitor of UPS, may counteract the extensive myocardial infarction and increased inflammatory reaction into the hyperglycemic myocardium. Methods: Ventricular biopsy specimens from 16 nondiabetic and 18 type 2 diabetic patients presenting with unstable angina who underwent coronary artery bypass were collected during coronary bypass surgery. Ejection fraction (EF); myocardial performance index (MPI), which measures both systolic and diastolic function, immunostaining, and cardiac levels of nitrotyrosine; UPS activity; NFkB; and TNF-alpha were investigated in both ischemic human myocardium and heart tissue from STZ-hyperglycemic rats subject to a myocardial ischemia/reperfusion procedure. Results: We found that diabetic patients had higher MPI (P

We evaluated the role of sterol-regulatory element binding protein (SREBP)-1c/peroxisome proliferator activated receptor-gamma (PPARgamma) pathway on heart lipotoxicity in patients with metabolic syndrome (MS) and aortic stenosis (AS). Echocardiographic parameters of heart function and structural alterations of LV specimens were studied in patients with (n = 56) and without (n = 61) MS undergoing aortic valve replacement. Tissues were stained with hematoxylin-eosin (H and E) and oil red O for evidence of intramyocyte lipid accumulation. The specimens were also analyzed with PCR, Western blot, and immunohistochemical analysis for SREBP-1c and PPARgamma. Ejection fraction (EF) was lower in MS compared with patients without MS (P < 0.001); no difference was found in aortic orifice surface among the groups. H and E and oil red O staining of specimens from MS patients revealed several myocytes with intracellular accumulation of lipid, whereas these alterations were not detected in biopsies from patients without MS. Patients without MS have low levels and weak immunostaining of SREBP-1c and PPARgamma in heart specimens. In contrast, strong immunostaining and higher levels of SREBP-1c and PPARgamma were seen in biopsies from the MS patients. Moreover, we evidenced a significative correlation between both SREBP-1c and PPARgamma and EF and intramyocyte lipid accumulation (P < 0.001). SREBP-1c may contribute to heart dysfunction by promoting lipid accumulation within myocytes in MS patients with AS; SREBP-1c may do it by increasing the levels of PPARgamma protein.

We report a case of primary non-Hodgkin lymphoma of the breast as third metachronous neoplasm in the same patient. Primary non-Hodgkin lymphoma of the breast occurred about 2 years after endometrial cancer and 1 year after bladder cancer. The patient underwent quadrantectomy with level I-II axillary lymph nodes dissection plus rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy. Patient's health status gradually got worse and 11 months after surgery the patient died.

Objective and design: We tested here the effects of acute administration of an oxygen/ozone (O3) mixture on the myocardial tissutal damage following an ischemic event. Material or subjects: The study was done in Sprague-Daw- ley rats subjected to acute myocardial ischemia/reperfusion (I/R). Treatment: 100; 150; and 300 µg/kg oxygen/O3 mixture were insufflated intraperitoneally 1 h prior to I/R. Methods: Myocardial infarct size measurement and im- munhistochemistry or ELISA for nitrotyrosine, CD68, CD8, CD4 and caspase-3 were done. Results: I/R produced a marked damage in the rat left ventri- cle with an infarct size as percentage of the area at risk (IS/ AR) of ∼45 ± 4 %. Rats insufflated with a oxygen/O 3 mixture showed a significant 2-h cardio-protection (e. g. infarct size over area at risk for the dose of 300 µg/kg was ∼30 ± 3 %,) as compared with control rats (P

The effect of the non-selective, 1-aminoindan-1,5-dicarboxylic acid (AIDA), and selective (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone (JNJ16259685), metabotropic glutamate subtype 1 (mGlu1) receptor antagonists, on rat sciatic nerve chronic constrictive injury (CCI)-induced hyperalgesia, allodynia, spinal dorsal horn apoptosis, and gliosis was examined at 3 and 7 days post-injury. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), nestin, GFAP, and caspase-7 mRNA in the dorsal horn spinal cord by 3 days post-CCI. At 7 days post-CCI, only over-expression of bcl-2, nestin and GFAP mRNA was observed. Administration of AIDA reduced thermal hyperalgesia and mechanical allodynia at 3 and 7 days post-CCI; administration of JNJ16259685 reduced thermal hyperalgesia at 3 and 7 days post-CCI, but not mechanical allodynia. AIDA decreased the mRNA levels of bax, apaf-1, GFAP and caspase-7 genes. JNJ16259685 increased the mRNA levels of bcl-2 and GFAP gene, and decreased APAF-1 and caspases-7 genes. Inhibiting mGlu1 receptors also reduced TUNEL-positive profiles and immunohistochemical reactivity for caspase-7. We report here that despite inhibiting CCI-induced over-expression of pro-apoptotic genes in the spinal cord dorsal horn, the selective mGlu1 receptor antagonist JNJ16259685 exerted only a slight and transient allodynic effect. Moreover, JNJ16259685, but not the non-selective AIDA, increased astrogliosis which may account for its decreased analgesic efficacy. This study provides evidence that the contemporary and partial blockade of group I and likely ionotropic glutamate receptors may be a more suitable therapy than selective blockade of mGlu1 subtype receptors condition to decrease neuropathic pain symptoms. © 2008 Elsevier Ltd. All rights reserved.

We report a case of a primary non-Hodgkin lymphoma of the testis in a 74-year-old man presented with a 1-month history of testicular swelling. The patient was submitted to right inguinal orchidectomy for the definitive diagnosis. Light microscopy demonstrated sheets of lymphoma cells involving epididymis and rete testis, but mainly extended into testicular parenchyma. The malignant cells were large with scant cytoplasm and large vesicular nuclei, the classic appearance of a diffuse large B-cell lymphoma. The immunohistochemical study was carried out, with the tumour cells being intensively positive for CD45, CD20 and Ki67 nuclear proliferative antigen. Clinical and pathological features of this non-Hodgkin lymphoma are described and discussed.