Current Status of Partial Laryngeal Surgery for Advanced Laryngeal Cancer: When and Why?

PURPOSE OF REVIEW: This paper aims to evaluate the evolution and current status of partial laryngeal surgery in the treatment of advanced laryngeal cancer (LC). Specifically, recent progress in the selection of both patients and tumors, together with surgical and rehabilitation innovations, have contributed to balancing oncological control with the maintenance of quality of life in naïve and radiorecurrent patients. The main aspect is represented by the recognized role of open partial horizontal laryngectomies (OPHLs) in this new era of laryngeal cancer treatment. RECENT FINDINGS: Recent advancements highlight OPHLs' efficacy for conservative management of intermediate to advanced stages of LC. Innovations such as supratracheal partial laryngectomy have expanded surgical options, offering a modular approach to complex cases. Improved understanding of tumor biology, enhanced imaging techniques, and more precise preoperative planning have led to better patient outcomes, emphasizing the importance of a conservative function-preserving surgical treatment. These advancements reflect a broader trend towards individualized treatment plans that prioritize both survival and quality of life. OPHLs play an important role in current management of intermediate/advanced LC, effectively balancing oncological control with the preservation of laryngeal functions. Critical factors include meticulous patient and tumor selection, the impact of surgical and technological refinements on functional outcomes, and the necessity of a multidisciplinary approach in treatment planning. Current evidence justifies the use of these interventions in many intermediate T-stage laryngeal tumors, even at risk of upstaging on pathological examination. The oncological results, the preservation of laryngeal function and the laryngectomy-free survival achieved with OPHLs appear to be highly competitive with those of non surgical organ-preservation protocols, aiming to introduce a new standard in the LC treatment.

Reliability of large language models for advanced head and neck malignancies management: a comparison between ChatGPT 4 and Gemini Advanced.

PURPOSE: This study evaluates the efficacy of two advanced Large Language Models (LLMs), OpenAI's ChatGPT 4 and Google's Gemini Advanced, in providing treatment recommendations for head and neck oncology cases. The aim is to assess their utility in supporting multidisciplinary oncological evaluations and decision-making processes. METHODS: This comparative analysis examined the responses of ChatGPT 4 and Gemini Advanced to five hypothetical cases of head and neck cancer, each representing a different anatomical subsite. The responses were evaluated against the latest National Comprehensive Cancer Network (NCCN) guidelines by two blinded panels using the total disagreement score (TDS) and the artificial intelligence performance instrument (AIPI). Statistical assessments were performed using the Wilcoxon signed-rank test and the Friedman test. RESULTS: Both LLMs produced relevant treatment recommendations with ChatGPT 4 generally outperforming Gemini Advanced regarding adherence to guidelines and comprehensive treatment planning. ChatGPT 4 showed higher AIPI scores (median 3 [2-4]) compared to Gemini Advanced (median 2 [2-3]), indicating better overall performance. Notably, inconsistencies were observed in the management of induction chemotherapy and surgical decisions, such as neck dissection. CONCLUSIONS: While both LLMs demonstrated the potential to aid in the multidisciplinary management of head and neck oncology, discrepancies in certain critical areas highlight the need for further refinement. The study supports the growing role of AI in enhancing clinical decision-making but also emphasizes the necessity for continuous updates and validation against current clinical standards to integrate AI into healthcare practices fully.

Vascular endothelial growth factor overexpression does not enhance adipose stromal cell-induced protection on muscle damage in critical limb ischemia.

OBJECTIVES: Critical limb ischemia complicates peripheral artery disease leading to tissue damage and amputation. We hypothesized that modifying adipose stromal cells (ASCs) to overexpress human vascular endothelial growth factor 165 (VEGF) would limit ischemic muscle damage to a larger extent than nonmodified ASCs. APPROACH AND RESULTS: Rabbits with critical hindlimb ischemia were injected with allogeneic abdominal fat-derived ASCs transfected with plasmid-VEGF165 (ASCs-VEGF; n=10). Additional rabbits received nontransfected ASCs (ASCs; n=10) or vehicle (placebo; n=10). One month later, ASCs-VEGF rabbits exhibited significantly higher density of angiographically visible collaterals and capillaries versus placebo (both P<0.05) but not versus ASCs (both P=NS). Arteriolar density, however, was increased in both ASCs and ASCs-VEGF groups (both P<0.05 versus placebo). ASCs-VEGF and ASCs showed comparable post-treatment improvements in Doppler-assessed peak systolic velocity, blood pressure ratio, and resistance index. Ischemic lesions were found in 40% of the muscle samples in the placebo group, 19% in the ASCs-VEGF group, and 17% in the ASCs groups (both P<0.05 versus placebo, Fisher test). CONCLUSIONS: In a rabbit model of critical limb ischemia, intramuscular injection of ASCs genetically modified to overexpress VEGF increase angiographically visible collaterals and capillary density. However, both modified and nonmodified ASCs increase arteriolar density to a similar extent and afford equal protection against ischemia-induced muscle lesions. These results indicate that modifying ASCs to overexpress VEGF does not enhance the protective effect of ASCs, and that arteriolar proliferation plays a pivotal role in limiting the irreversible tissue damage of critical limb ischemia.

Emerging concepts in heart failure management and treatment: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction.

The role of sodium-glucose cotransporter 2 inhibitors (SLTG2i), developed initially as glucose-lowering agents, has represented a novelty in patients with heart failure (HF) and reduced ejection fraction (HFrEF) since dapagliflozin (DAPA-HF study) and empagliflozin (EMPEROR-Reduced study) were able to reduce morbidity and mortality in this setting regardless of the presence or absence of diabetes. In previous large clinical trials (EMPA-REG OUTCOME study, CANVAS, DECLARE-TIMI 58), SGLT2i have been shown to attenuate HF progression expressed by reducing the risk of HF hospitalizations in patients with type 2 diabetes mellitus mostly without HF at baseline. This benefit was then corroborated with positive results in HF outcomes (cardiovascular mortality and HF hospitalizations) in patients with HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials. Several biological mechanisms apart from the glycosuria are attributed to these agents in this last context, including anti-inflammatory effects, reduction of fibrosis and apoptosis, improvement of myocardial metabolism, mitochondrial function optimization, and oxidative stress protection. Moreover, SGLT2i can also improve ventricular loading conditions by forcing diuresis and natriuresis, and by enhancing vascular and renal function. In addition, SGLT2i can reduce myocardial passive stiffness (diastolic function) by enforcing the phosphorylation of myofilament modulatory proteins. This article provided an overview of the main pathophysiological characteristics of HFpEF and of the diverse mechanisms of action of SGLT2i in this setting. The supporting clinical evidence of SGLT2i in HFpEF (EMPEROR-Preserved and DELIVER trials) is also reviewed. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.

Effect of vascular endothelial growth factor gene transfer on infarct size, left ventricular function and myocardial perfusion in sheep after 2 months of coronary artery occlusion.

BACKGROUND: In large mammalian models of acute myocardial infarction (AMI), plasmid-mediated vascular endothelial growth factor (pVEGF) gene transfer has been shown to induce angio-arteriogenesis, proliferation of myocyte precursors and adult cardiomyocyte mitosis, reducing infarct size at 15 days after coronary artery occlusion. However, it is unknown whether these effects persist at longer follow-up times, nor how they affect cardiac performance. We thus assessed infarct size, left ventricular (LV) function and perfusion in 2-month-old ovine AMI. METHODS: Adult sheep with coronary artery occlusion were randomized to blindly receive ten intramyocardial injections of 3.8 mg of pVEGF or empty plasmid distributed at the infarct border. Three and 60 days later, LV perfusion (single-photon emission computed tomography) and function (stress echocardiography) were assessed. Finally, hemodynamics (LV catheterization), scar size and peri-infarct histology were studied. RESULTS: Infarct size was 30% smaller in pVEGF-treated sheep (23.6 ± 1.9% versus 32.7 ± 2.7% of the LV; p < 0.02). Percentage fractional shortening and wall thickening at the infarct border improved after pVEGF, as did myocardial perfusion and LV wall motion under pharmacological stress. Global LV function did not differ between groups, although the force-frequency response was preserved in pVEGF group and lost in placebo animals. These effects were associated with angio-arteriogenesis and proliferation of cardiomyocyte precursors. CONCLUSIONS: In sheep with AMI, pVEGF gene transfer affords long-term infarct size reduction, yielding regional LV function and perfusion improvement and reducing remodeling progression. These results suggest the potential usefulness of this approach in the clinical setting.

Transoral Approach to Parotid Tumors: A Review of the Literature.

Different surgical techniques have been proposed for parapharyngeal space tumors, including transcervical, transparotid, trans-mandibular, infratemporal, and transoral. The choice of the correct approach depends on the size, localization and nature of the tumor. The transoral approach can be used for benign prestyloid masses, such as tumors of the deep lobe of the parotid gland. It guarantees a short hospitalization without skin scars. The narrowed access represents the main limitation of this technique. This review will summarize and analyze the current knowledge about the transoral approach to parotid lesions. Thirty-seven studies were included in a qualitative and quantitative synthesis. The novelty of this review is the quantitative analyses of the clinical data reported in the included studies.

Long-term effects of growth hormone on infarct size and left ventricular function in sheep with coronary artery occlusion.

The effects of growth hormone (GH) on infarct size and left ventricular (LV) function in experimental acute myocardial infarction (AMI) have been controversial. Moreover, little, if any, information exists regarding long-term evaluation of therapeutic doses of GH in large mammalian models of AMI. We therefore aimed to assess the effect of therapeutic doses of GH over 3.5 months on infarct size and heart function in sheep with AMI. After coronary artery ligation, sheep received subcutaneous human GH 8 IU/d (n = 8) or vehicle (n = 8) over 100 days. Infarct area was similar in GH (16.9% +/- 3% of LV area) and placebo (16.5% +/- 3.7%, P = not significant) sheep. At 3 days of treatment onset, but not at later times, GH sheep had higher LV shortening fraction (30.7% +/- 3.5% vs. 24.8% +/- 6.1%, P < 0.04), systolic anterior wall thickness (10.1 +/- 0.8 vs. 8.6 +/- 1.2 mm, P < 0.02), and cardiac index (3.8 +/- 0.6 vs. 2.8 +/- 0.7 L x min x m, P < 0.01). This evolution of function parameters paralleled that of serum insulin-like growth factor 1 levels, which differed significantly only during the first week, suggesting a direct effect of GH on LV contractility. These results may suggest the usefulness of therapeutic doses of GH at the early phases of AMI but do not support maintaining the treatment for longer time.

Sol-gel silicon alkoxides-polyethylene glycol derived hybrids for drug delivery systems.

PURPOSE: The potential application of hybrid systems based on silicon alkoxides and polyethylene glycol 400 as drug delivery systems was studied. METHODS: They were synthesized using the sol-gel technique, using ketoprofen as a model drug. The preparation of the materials and their characterization by X-ray diffraction, infrared spectroscopy, thermogravimetric analysis are reported. Drug loading was performed during the gelation of the sols. Drug release studies were performed at pH 1.2 and 7.5 mimicking gastrointestinal environments. RESULTS: Drug release was affected by the presence of polyethylene glycol in the formulation: a faster release was observed for polyethylene glycol hybrids. CONCLUSIONS: The results suggest that these devices should guarantee long durability after implantation and could be suitable for sustained release: after a first period of release by diffusion, complete release will be reached by bioerosion of the matrix.

Thermal-induced hydrophilicity enhancement of titanium dental implant surfaces.

Titanium surface characteristics, including microtopography, chemical composition, and wettability, are essential features to achieve osseointegration of dental implants, but the choice of a particular surface topography is still a debated topic among clinicians. An increased level of implant surface hydrophilicity has been demonstrated to ameliorate osseointegration and shorten healing times. The aim of this work is to develop and test a suitable thermal-based method to enhance titanium surface wettability without modifying other characteristics of the implant surface. For this function, titanium discs with different surface topography have been thermally treated by testing different temperatures and excluding those that led to evident chromatic and morphological modifications. The selected surface gain in wettability after the treatment was assessed through contact angle measurement, chemistry modifications through x-ray photoelectron spectroscopy (XPS) analysis, and microtopography through scanning electron microscopy (SEM). Results showed a great enhancement in hydrophilicity on the tested surfaces without any other modification in terms of surface chemical composition and topography. A possible limitation of this method could be the persistent, although relatively slow, biological aging of the surfaces after the treatment. The present findings indicate that the described treatment could be a safe and effective method to enhance dental titanium hydrophilicity and thus its biological performance.

Ag-functionalized nanocrystalline cellulose for paper preservation and strengthening.

Waste paper is an environmentally friendly source of cellulosic material. Here we propose a new treatment based on nanocrystalline cellulose (CNC) for paper preservation and consolidation. Suspensions of CNC were prepared by sulfuric acid hydrolysis using waste paper as cellulose source (CNCWP) and compared with CNC from cotton linter (CNCCL). Both CNCs were obtained with good yield, showing high crystallinity index and comparable morphology, as demonstrated by DLS-ELS, XRD, FTIR, Raman and TEM analyses. CNCs were mixed with silver nanoparticles (CNC/Ag) and their biocidal activity was tested against Escherichia coli and Bacillus subtilis, measuring the minimum inhibitory concentration. CNCs were exploited as treatments for biocidal activity and consolidation on Whatman paper. The presence of silver nanoparticles doesn't affect aesthetic appearance of the original paper and prevents the growth of Aspergillus niger fungus. Mechanical tests demonstrated that the coatings by CNC based products improve stretch and toughness of the paper support.

High-dose intramyocardial HMGB1 induces long-term cardioprotection in sheep with myocardial infarction.

In rodents with acute myocardial infarction (AMI), high mobility group box 1 (HMGB1) injection has produced controversial results. Given the lack of data in large mammals, we searched the dose that would promote angiogenesis and expression of specific regenerative genes in sheep with AMI (protocol 1) and, subsequently, use this dose to study long-term effects on infarct size and left ventricular (LV) function (protocol 2). Protocol 1: Sheep with AMI received 250 µg (high-dose, n = 7), 25 µg (low-dose, n = 7) HMGB1, or PBS (placebo, n = 7) in 10 intramyocardial injections (0.2 ml each) in the peri-infarct area. Seven days later, only the high-HMGB1-dose group exhibited higher microvascular densities, Ki67-positive cardiomyocytes, and overexpression of VEGF, Ckit, Tbx20, Nkx2.5, and Gata4. Protocol 2: Sheep with AMI received HMGB1 250 µg (n = 6) or PBS (n = 6). At 60 days, HMGB1-treated sheep showed smaller infarcts (8.5 ± 2.11 vs. 12.2 ± 1.97% LV area, P < 0.05, ANOVA-Bonferroni) and higher microvascular density (capillaries, 1798 ± 252 vs. 1266 ± 250/mm2; arterioles, 18.3 ± 3.9 vs. 11.7 ± 2.2/mm2; both P < 0.01). Echocardiographic LV ejection fraction, circumferential shortening, and wall thickening increased from day 3 to 60 with HMGB1 (all P < 0.05). Conclusion: in ovine AMI, high-dose HMGB1 induces angio-arteriogenesis, reduces infarct size, and improves LV function at 2 months post-treatment.

Effect of poly (l-lactic acid) scaffolds seeded with aligned diaphragmatic myoblasts overexpressing connexin-43 on infarct size and ventricular function in sheep with acute coronary occlusion.

Diaphragmatic myoblasts (DM) are stem cells of the diaphragm, a muscle displaying high resistance to stress and exhaustion. We hypothesized that DM modified to overexpress connexin-43 (cx43), seeded on aligned poly (l-lactic acid) (PLLA) sheets would decrease infarct size and improve ventricular function in sheep with acute myocardial infarction (AMI). Sheep with AMI received PLLA sheets without DM (PLLA group), sheets with DM (PLLA-DM group), sheets with DM overexpressing cx43 (PLLA-DMcx43) or no treatment (control group, n = 6 per group). Infarct size (cardiac magnetic resonance) decreased ∼25% in PLLA-DMcx43 [from 8.2 ± 0.6 ml (day 2) to 6.5 ± 0.7 ml (day 45), p < .01, ANOVA-Bonferroni] but not in the other groups. Ejection fraction (EF%) (echocardiography) at 3 days post-AMI fell significantly in all groups. At 45 days, PLLA-DM y PLLA-DMcx43 recovered their EF% to pre-AMI values (PLLA-DM: 61.1 ± 0.5% vs. 58.9 ± 3.3%, p = NS; PLLA-DMcx43: 64.6 ± 2.9% vs. 56.9 ± 2.4%, p = NS), but not in control (56.8 ± 2.0% vs. 43.8 ± 1.1%, p < .01) and PLLA (65.7 ± 2.1% vs. 56.6 ± 4.8%, p < .01). Capillary density was higher (p < .05) in PLLA-DMcx43 group than in the remaining groups. In conclusion, PLLA-DMcx43 reduces infarct size in sheep with AMI. PLLA-DMcx43 and PLLA-DM improve ventricular function similarly. Given its safety and feasibility, this novel approach may prove beneficial in the clinic.

Comparison of Environmental Scanning Electron Microscopy in Low Vacuum or wet mode for the investigation of cell biomaterial interactions.

AIM: The aim of the present study was to investigate the efficacy of environmental scanning electron microscopy (ESEM), in low vacuum mode (LV-ESEM) and in wet mode (wet-ESEM) in the assessment of cell-material interactions. METHODS: Mouse calvaria MC3T3 cells (ATCC) were seeded on commercially pure machined titanium discs of 10 mm diameter in Dulbecco modified MEM, 10% Fetal Bovine Serum, 1% Penicillin and Streptomycin and 1% Glutamine. Samples were then processed for microscope observation by rinse in Phosphate Buffer saline and fixation in 4.5% Glutaraldehyde. Samples were then rinsed in Sodium Cacodylate buffer and observed or dehydrated in alcohol prior to LV-ESEM observation. Fresh samples in 0.9% NaCl solution were observed in wet- ESEM. RESULTS: No significant loss of detail was observed when dehydrated or non dehydrated samples were analysed at LV-ESEM.The observation of fresh samples in wet-ESEM however proved difficult for the need to eliminate water which forms a layer covering the sample, thus hiding cell surface details. When reducing the vapor pressure in the chamber, the layer evaporated and NaCl immediately started to precipitate and cells collapsed, thus no further investigation was possible. CONCLUSIONS: The use of low vacuum-ESEM after cell fixation, but without dehydration or gold sputter coating proved a viable alternative to traditional high vacuum SEM observation.

Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia-Inducible Factor 1-α (HIF1-α) in an Ovine Model of Acute Myocardial Infarction.

BACKGROUND: Bone marrow mesenchymal stromal cells (BMMSCs) are cardioprotective in acute myocardial infarction (AMI) because of release of paracrine angiogenic and prosurvival factors. Hypoxia-inducible factor 1-α (HIF1-α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSCs engineered to overexpress mutant, oxygen-resistant HIF1-α would confer greater cardioprotection than nontransfected BMMSCs in sheep with AMI. METHODS AND RESULTS: Allogeneic BMMSCs transfected with a minicircle vector encoding mutant HIF1-α (BMMSC-HIF) were injected in the peri-infarct of sheep (n=6) undergoing coronary occlusion. Over 2 months, infarct volume measured by cardiac magnetic resonance (CMR) imaging decreased by 71.7±1.3% (P<0.001), and left ventricular (LV) percent ejection fraction (%EF) increased near 2-fold (P<0.001) in the presence of markedly decreased end-systolic volume. Sheep receiving nontransfected BMMSCs (BMMSC; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo-treated animals (n=6), neither parameters changed over time. HIF1-α-transfected BMMSCs (BMMSC-HIF) induced angio-/arteriogenesis and decreased apoptosis by HIF1-mediated overexpression of erythropoietin, inducible nitrous oxide synthase, vascular endothelial growth factor, and angiopoietin-1. Cell tracking using paramagnetic iron nanoparticles in 12 additional sheep revealed enhanced long-term retention of BMMSC-HIF. CONCLUSIONS: Intramyocardial delivery of BMMSC-HIF reduced infarct size and improved LV systolic performance compared to BMMSC, attributed to increased neovascularization and cardioprotective effects induced by HIF1-mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSCs for allogeneic application, this treatment may be potentially useful in the clinic.

Arteriogenesis induced by intramyocardial vascular endothelial growth factor 165 gene transfer in chronically ischemic pigs.

Exogenous vascular endothelial growth factor (VEGF) improves tissue perfusion in large animals and humans with chronic myocardial ischemia. Because tissue perfusion is mainly dependent on the arteriolar tree, we hypothesized that the neovascularizing effect of VEGF should include arteriogenesis, an effect not as yet described in large mammalian models of myocardial ischemia. In the present study we investigated the effect of intramyocardial plasmid-mediated human VEGF(165) gene transfer (pVEGF(165)) on the proliferation of vessels with smooth muscle in a pig model of myocardial ischemia. In addition, we assessed the effect of treatment on capillary growth, myocardial perfusion, myocardial function and collateralization. Three weeks after positioning of an Ameroid constrictor (Research Instruments SW, Escondido, CA) in the left circumflex artery, pigs underwent basal perfusion (single-photon emission computed tomography [SPECT] with (99m)Tc-sestamibi) and regional function (echocardiography) studies at rest and under dobutamine stress, and were then randomly assigned to receive transepicardial injection of pVEGF(165) 3.8 mg (n = 8) or placebo (empty plasmid, n = 8). All experimental steps and data analysis were done in a blinded fashion. Five weeks later, pVEGF(165)-treated pigs showed a significantly higher density of small (8-50 microm in diameter) vessels with smooth muscle, higher density of capillaries, and improved myocardial perfusion. These results indicate an arteriogenic effect of VEGF in a large mammalian model of myocardial ischemia and encourage the use of VEGF to promote arteriolar growth in patients with severe coronary artery disease.

Natamycin based sol-gel antimicrobial coatings on polylactic acid films for food packaging.

In this work a comprehensive study on a new active packaging obtained by a hybrid organic-inorganic coating with antimicrobial properties was carried out. The packaging system based on polylactic acid was realised by sol-gel processing, employing tetraethoxysilane as a precursor of the inorganic phase and polyvinyl alcohol as the organic component, and incorporating natamycin as the active agent. Films with different organic-inorganic ratios (in a range between 1:19 and 1:4) were prepared, and the amount of antimycotic entrapped was found to be modulated by the sol composition, and was between 0.18 and 0.25mg/dm(2). FTIR microspectroscopic measurements were used to characterise the prepared coatings. The antifungal properties of the films were investigated against mould growth on the surface of commercial semi-soft cheese. The release of natamycin from the films to ethanol 50% (v/v) was studied by means of HPLC UV-DAD. The maximal level released was about 0.105 mg/dm(2), which is far below the value allowed by legislation.

Synthesis and characterization of nanocrystalline TiO2 with application as photoactive coating on stones.

UNLABELLED: Self-cleaning photocatalytic coatings for biocalcarenite stones, based on TiO2 nanoparticles obtained by sol-gel processes at different pH values and also adding gold particles, have been investigated. The selected test material is a biocalcarenite named "pietra di Lecce" (Lecce stone), outcropping in Southern Italy. Scanning electron microscopy with energy-dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, and Raman investigations were carried out to characterize the TiO2 nanoparticles and coatings. Nanocrystalline anatase and, to a lesser extent, brookite phases are obtained. Photocatalytic activity of the TiO2 sols and of the coatings on "pietra di Lecce" was assessed under ultraviolet irradiation, monitoring methyl orange (MeO) dye degradation as a function of time. To evaluate the harmlessness of the treatment, colorimetric tests and water absorption by capillarity were performed. The results show good photodegradation rates for titania nanosols, particularly when putting in Au particles, whereas a satisfactory chromatic compatibility between the sol and the surface of the calcarenite is found only without Au addition. HIGHLIGHTS: Sols of nanocrystalline titania at different pH values and with Au particles were prepared and characterized. Satisfactory photodegradation of MeO by the sols in solution and on calcarenite-coated surfaces is obtained. The addition of Au particles improves the photodegradation activity but gives poor chromatic results on "pietra di Lecce."

Combined VEGF gene transfer and erythropoietin in ovine reperfused myocardial infarction.

BACKGROUND: In reperfused acute myocardial infarction (RAMI), cardioprotective treatments may enhance myocardial salvage and hence reduce the area of necrosis. Based on studies showing that plasmid-mediated vascular endothelial growth factor (pVEGF) gene transfer reduces infarct size by combining angio-arteriogenic and cardiomyogenic effects and that erythropoietin (EPO) exerts anti-apoptotic actions in animal models of AMI, we aimed to assess if their association would reduce infarct size to a larger extent than any of them individually in a large mammalian model of RAMI. METHODS: Adult sheep subjected to 90-minute coronary artery occlusion received upon reperfusion intramyocardial pVEGF 3.8 mg plus intravenous EPO 1000 IU/kg (n=8), pVEGF (n=8), EPO (n=8) or placebo (n=8). RESULTS: Fifteen days after treatment, infarct size was smaller in the 3 treatment groups (pVEGF+EPO: 8 ± 1 %; pVEGF: 16 ± 5 %; EPO: 13 ± 4 %) compared to placebo (25 ± 7 %, p<0.001). However, in the EPO+VEGF group infarct size was significantly smaller than in the groups receiving EPO or VEGF individually (p<0.05). DNA fragmentation, a hallmark of late apoptosis, was significantly lower in sheep receiving EPO. The combined treatment, while not affecting global left ventricular performance, improved regional peri-infarct function and prevented over-time expansion of the post-infarct perfusion defect. CONCLUSIONS: Combined pVEGF and EPO treatment might be clinically useful to enhance the benefits of early revascularization in patients with acute myocardial infarction.

Reference values for echocardiographic parameters and indexes of left ventricular function in healthy, young adult sheep used in translational research: comparison with standardized values in humans.

Ovine models of ischemic heart disease and cardiac failure are increasingly used in translational research. However, reliable extrapolation of the results to the clinical setting requires knowing if ovine normal left ventricular (LV) function is comparable to that of humans. We thus assessed for echocardiographic LV dimensions and indexes in a large normal adult sheep population and compared them with standardized values in normal human adults. Bidimensional and tissue Doppler echocardiograms were performed in 69 young adult Corriedale sheep under light sedation. LV dimensions and indexes of systolic and diastolic function were measured. Absolute and body surface areanormalized values were compared to those for normal adult humans and their statistical distribution was assessed. Normalized dimensions (except for end diastolic diameter) as well as ejection fraction and fractional shortening fell within the ranges established by the American Society of Echocardiography and European Association of Echocardiography for normal adult humans. Normalized end diastolic diameter exceeded the upper normal limit but got close to it when correcting for the higher heart mass/body surface area ratio of sheep with respect to humans. Diastolic parameters also fell within normal human ranges except for a slightly lower mitral deceleration time. All values exhibited a Gaussian distribution. We conclude that echocardiographic parameters of systolic and diastolic LV performance in young adult sheep can be reliably extrapolated to the adult human, thus supporting the use of ovine models of human heart disease in translational research.

High-dose erythropoietin has no long-term protective effects in sheep with reperfused myocardial infarction.

High-dose erythropoietin has been claimed to be cardioprotective in experimental acute myocardial infarction. In large mammals, however, results are controversial and long-term follow-up data are lacking. We thus assessed the long-term effects of high-dose erythropoietin on left ventricular infarct size and function in an ovine model of reperfused myocardial infarction. After 90 minutes of coronary occlusion followed by reperfusion, sheep received recombinant human erythropoietin (rhEPO) 3000 units/kg on 3 consecutive days (rhEPO group, n=7) or vehicle (placebo group, n=6). Ten weeks later, ventricular function was assessed by echocardiography and catheterization. Infarct size, evaluated as percent fibrotic myocardium (morphometry) and by hydroxyproline quantification, was similar in both groups (morphometry: rhEPO: 22.1 +/- 5.5%, placebo: 18.1 +/- 3.3%, P not significant; hydroxyproline: rhEPO: 6.6 +/- 1.3 microg/mg wet weight, placebo: 7.1 +/- 0.9 microg/mg, P not significant). Ventricular function was diminished in the rhEPO group, as indicated by lower septal wall thickening at the infarct border zone (rhEPO: -1.9 +/- 16.4%, placebo: 20.5 +/- 17%, P<0.04), higher end systolic volume (rhEPO: 47 +/- 14.3 mL, placebo: 32.6 +/- 7.3 mL, P<0.05), and higher end diastolic pressure (rhEPO: 17 +/- 6.5 mm Hg, placebo: 10.1 +/- 2.8 mm Hg, P<0.03). In the rhEPO group, left ventricular endocardial area was larger, suggesting dilatation. High-dose erythropoietin has no cardioprotective effects in sheep with reperfused myocardial infarction.