MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs.

Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.

Persistence of vitamin D deficiency among Italian patients with acute myocardial infarction.

BACKGROUND AND AIMS: Vitamin D deficiency is a common cardiovascular risk factor associated with the development of atherosclerosis. We evaluated changes in 25(OH)D concentrations in 1510 patients with acute myocardial infarction (AMI) over a long observation period, including the COVID-19 pandemic. METHODS AND RESULTS: Patients were separated into four groups according to the year of enrolment, group 1 (2009-2010), group 2 (2014-2016), group 3 (2017-2019), and group 4 (2020-2022). The median 25(OH)D concentration in the overall cohort was 17.15 (10.3-24.7) ng/mL. The median plasma concentrations of 25(OH)D for groups 1, 2, 3, and 4 were 14.45 (7.73-22.58) ng/mL, 17.3 ng/mL (10.33-24.2), 18.95 (11.6-26.73) ng/mL and 19.05 (12.5-27.3) ng/mL, respectively. Although 25(OH)D levels increased over the years, the prevalence of vitamin D deficiency remained high in each group (68.4%, 61.4%, 53.8%, and 52% respectively). Hypovitaminosis D was predicted by the season influence (OR:2.03, p < 0.0001), higher body mass index (OR:1.25; p = 0.001), diabetes mellitus (OR:1.54; p = 0.001), smoking (OR:1.47; p = 0.001), older age (OR:1.07; p = 0.008), higher triglycerides levels (OR:1.02; p = 0.01), and female gender (OR:1.3; p = 0.038). After multivariable adjustment, vitamin D ≤ 20 ng/mL was an independent predictor of mortality. CONCLUSION: Vitamin D deficiency is highly prevalent and persistent in patients with AMI despite a trend towards increasing 25(OH)D concentrations over the years. The frequent lockdowns did not reduce the levels of 25(OH)D in the fourth group. Low levels of 25(OH)D are an independent predictor of mortality.

Effects of Simvastatin on Fetal Cardiac Impairment in the Diaphragmatic Experimental Hernia Model.

BACKGROUND: Statins and sildenafil have been shown to exert beneficial effects in cardiac injury. We hypothesized that antenatal maternal administration of simvastatin and/or sildenafil might also promote benefits in cardiac remodeling of congenital diaphragmatic hernia (CDH). Therefore, we performed micro-CT image analysis and histology of the heart after antennal treatment in experimental nitrofen-induced CDH. METHODS: At 9.5 days post conception (dpc), pregnant rats were exposed to nitrofen. At 16 and 20 dpc fetuses were treated with simvastatin and/or sildenafil. At 21 dpc postmortem micro-CT and autopsy were performed. RESULTS: All nitrofen-treated fetuses had a lower birth weight compared to controls; in the simvastatin-treated group, a significant improvement in CDH was noted. Impairment of the lung and liver was also noted in CDH. Compared to controls, CDH rats showed lower ventricular mass, with greater left ventricular thickness; simvastatin decreased the ventricular mass and improved wall thickness. CDH rats exhibited myocardial hypotrophy, severe vascular depression in the left ventricle, and intense interstitial edema compared to controls and nitrofen-exposed animals without CDH. In CDH, the cardiac morphology appeared deformed with left ventricular wall verticalization. Simvastatin improved cardiac myocyte appearance and heart morphology. CONCLUSION: The potential to treat CDH with antenatal simvastatin may improve the management of this malformation.

Hypertrophic osteoarthropathy mimicking a reactive arthritis: a case report and review of the literature.

BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and periosteal tissues of the extremities. It can be a rare hereditary disease (pachydermoperiostosis) or can be secondary to various diseases, though mostly lung malignancies. Here, we report an unusual clinical presentation of HOA. CASE PRESENTATION: A 77-year-old man presented with fever, diarrhea, and an oligoarthritis involving the left knee and the ankles. Since left knee synovial fluid aspiration revealed an aseptic synovitis and Clostridium Difficile toxin was detectable in stool samples, a reactive arthritis secondary to a Clostridium Difficile induced colitis was initially suspected. However, the presence of a worsened digital clubbing and the lack of a good clinical response to steroid therapy led us to perform a radionuclide bone scanning, which revealed HOA. This turned out to be associated with a lepidic predominant lung adenocarcinoma, which was clinically and radiologically difficult to distinguish from a relapse of pneumonia. CONCLUSION: Consistent with the literature, HOA tends to have a variable clinical presentation, mimicking that of various rheumatic diseases. This clinical case shows that HOA can present as a presumptive acute reactive arthritis, and it highlights the importance of patient's follow-up in the differential diagnosis of inflammatory arthritis, especially when a worsened digital clubbing is present.

Tailored resections in oral and oropharyngeal cancer using narrow band imaging.

PURPOSE: In a previous pilot study we observed that intra-operative narrow-band imaging (NBI) helps achieve clear superficial resection margins. The aim of this study was to verify if the use of intra-operative NBI can help to obtain tailored resections and if it is influenced by the lesion site, aspects not investigated in our previous study. MATERIALS AND METHODS: The resection margins of 39 oral and 22 oropharyngeal squamous cell carcinomas were first set at 1.5cm from the macroscopic lesion boundary (white light, WL, tattoo). Then, the superficial tumor extension was more precisely defined with NBI, giving rise to three possible situations: NBI tattoo larger than the WL tattoo, NBI tattoo coinciding with the WL tattoo, or NBI tattoo smaller than the WL tattoo. For each of these situations the space comprised between the NBI and WL tattoos was defined "NBI positive", "NBI null", and "NBI negative", respectively. Resections were performed following the outer tattoo. The number of clear superficial resection margins, and the pathological response on the "NBI-positive" and the "NBI-negative" areas were recorded. RESULTS: We obtained 80.3% negative superficial resection margins. NBI provided a more precise definition of superficial tumor extension in 43 patients. Sensitivity, specificity, positive and negative predictive values were 94.4%, 64%, 79.1% and 88.9%, respectively; a test of proportions demonstrated they were not influenced by tumor site. CONCLUSIONS: NBI could allow for real-time definition of superficial tumor extension with possible tailored resections and fewer positive superficial resection margins; it is not influenced by tumor site.

Pulmonary recurrence from prostate cancer and biochemical remission after metastasis directed therapy. A case report.

We report a case of a 69-years-old man who presented with a solitary 1 cm nodule in the lower lobe of the left lung almost 3 years after radical prostatectomy for pT3aN0M0, Gleason score 4+3 disease, without evidence of osseous or lymphatic spread. Surgical resection of the pulmonary lobe confirmed the metastatic nature of the lesion, with subsequent reduction of serum PSA to undetectable levels. After 2 years from the metastasis resection, serum PSA is still undetectable, without the necessity of additional treatments. Solitary pulmonary metastases from prostate cancer (Pca) are rare in clinical practice, with only 29 previous cases described besides the one that we present.

Neoplastic Embolization from Cardiac Papillary Fibroelastoma with Unusual Presentation: A Case Report.

Papillary fibroelastoma is the second most frequent primary tumor of the heart. We report the case of a cardiac papillary fibroelastoma, arising from the interatrial septum, symptomatic from distal embolization to lower limb arteries. Such a clinical presentation is extremely infrequent for cardiac papillary fibroelastomas. Moreover, the site of origin not from cardiac valves and the pathogenetic mechanism underlying the clinical manifestation both represent peculiar additional findings of our case.

Myocardial effects of fetal endoscopic tracheal occlusion in lambs with CDH.

INTRODUCTION: Fetal endoscopic tracheal occlusion in congenital diaphragmatic hernia (CDH) may reduce pulmonary hypertension and ameliorate postnatal cardiac output. The effects of sustained early (ETO) and late (LTO) tracheal occlusion on left ventricular (LV) cells in the lamb model have not been described. MATERIALS AND METHODS: CDH was created in lambs at 70 days' gestation (term = 145 days). ETO (85 days) or LTO (105 days) was sustained till term. After cesarean section (140 days) fetuses were euthanized and hearts harvested. LV myocardial cells were studied by histological and immunofluorescence (TGF-beta 1, endothelin-1) assays in CDH, ETO, LTO, and the control group (two subjects per group). Small intramyocardial arteries were evaluated by traditional histology. RESULTS: LV myocardial histology in CDH and LTO was similar. ETO-induced LV myocardial cell enlargement and increased endothelin-1 and TGF-beta 1 staining; a weaker immunofluorescence signal was observed in LTO compared with ETO. Myocardial vascular wall thickness was greater in CDH than in controls. ETO was associated with a vascular wall thickness within the range of controls. CONCLUSION: With only two fetuses in each group, only an explorative evaluation was possible. The time point at which TO is performed seems to have an effect on cardiac morphology. Functional studies as well as confirmation in clinical samples are mandatory.

Cardiac Adaptation to Severe Congenital Diaphragmatic Hernia.

OBJECTIVE: Prenatal heart adaptations to congenital diaphragmatic hernia (CDH) could help define postnatal outcome. METHODS: We retrospectively analyzed post-mortem tissues from fetuses with severe CDH (n = 7). Histology and immunohistochemical distribution of desmin, muscle actin [HHF35], endothelin-1 [ET-1] and TGF-ß were evaluated. RESULTS: In the atrium, desmin, HHF35, ET-1, TGF-ß were found expressed only in preterm CDH. Dishomogeneous ventricular distribution of cardiac growth factors were detected in term CDH. The cardiomyocyte nucleus/cytoplasmatic ratio in CDH was higher compared with controls (p = 0.01). Small intramyocardial artery density and vascular wall thickness was increased in CDH compared with controls (p = 0.03 and p < 0.01). In comparison with the ventricles, the interventricular septum showed a greater vessel density (p = 0.01) and a greater vascular wall thickness, particularly compared with the CDH right ventricle (p = 0.02). CONCLUSION: Left ventricle immaturity seems to be a cardiac adaptive response of severe CDH in utero.

Overview and Comparison of Infectious Endocarditis and Non-infectious Endocarditis: A Review of 814 Autoptic Cases.

AIM: We examined evidence on infective and non-infective endocarditis obtained from a database of 50,403 clinical autopsies performed at an Italian general hospital between January 1983 and December 2006. MATERIALS AND METHODS: Out of 814 endocarditis cases, 409 were of infective endocarditis (IE) and 405 non-infective (NIE). The median age at the time of death was 78 years for those with IE and 83 for those with NIE. Data were collected on gender, clinical history, comorbidities, kind of affected valve (non-prosthetic/mechanical/biological), pathological features of endocarditis, endocarditis complications and microbiological agents. RESULTS: The diagnosis of IE was frequently missed and these conditions were often complicated by cardiovascular events. IE was more common among patients with prior valve infection or cardiovascular surgery, while malignancies were frequent comorbidities of NIE. CONCLUSION: In general, we found several data that differ from those generally present in the scientific literature, and this could be explained by the fact that data on IE and NIE are generally obtained from surgical and clinical databases, while we analysed only autoptic cases.

Fatal Septic Shock in a Patient with Hemophagocytic Lymphohistiocytosis Associated with an Infectious Mononucleosis.

The authors describe the case of a young woman who developed a clinical pictures resembling a septic shock-related multiple organ dysfunction syndrome a couple of months after having been diagnosed suffering from a hemophagocytic lymphohistiocytosis associated with an infectious mononucleosis. Despite the aggressive treatment, which included antibiotics, vasopressors, IV immunoglobulins, and the use of an extracorporeal device aimed to remove mediators released both during sepsis and the cytokine storm determined by the hemophagocytic lymphohistiocytosis, the patient died. At the autopsy, an extremely uncommon aggressive lymphoma of Epstein-Barr virus-positive T-lymphocytes with systemic involvement was discovered.

[Peripheral embolization and rapid growth of papillary fibroelastoma in a young woman]. / Embolizzazione periferica e rapida ricrescita di fibroelastoma papillare in una giovane donna.

Papillary fibroelastoma, a benign cardiac tumor, is a rare clinical condition. Before the echocardiography era, the diagnosis was often occasional, especially during other cardiac procedures; but nowadays it has improved with the advent of higher-resolution imaging technology. The clinical presentation can vary from asymptomatic to severe complications such as cerebrovascular or ischemic events due to tumor embolization.We present the case of a 33-year-old female with a papillary fibroelastoma on the anterior leaflet of the mitral valve undergoing clinical examination for claudicatio intermittens. An occlusion of the left common femoral artery was present. The diagnosis was made posteriorly after embolectomy. All cardiac imaging investigations were negative. The heart team decided a strict echocardiographic follow-up every 3 months, and after the first visit a pedunculated mass was detected on the anterior mitral leaflet. The surgical management included urgent resection of the tumor on cardiopulmonary bypass using a minimally invasive approach via a right anterior minithoracotomy. The postoperative course was uneventful. We emphasize the need for surgical treatment given the potential risk of relapse. When no mass is detected on imaging, a strict echocardiographic follow-up and antiplatelet therapy are mandatory.

A case report of hyponatremia after surgery for Conn's adenoma.

Primary aldosteronism (PA), also known as Conn's syndrome, is a frequent cause of secondary hypertension. If PA is due to a documented unilateral adrenal adenoma, adrenalectomy is the treatment of choice. Endocrine Society guidelines suggest monitoring potassium after adrenalectomy, while there is no mention of sodium disorders after surgery. Here we report the case of a patient with Conn's syndrome who developed hyponatremia after surgery. This was an unexpected event in the course of the treatment, which sheds light on the fact that low levels of aldosterone strongly influence sodium concentration, and advises clinicians to monitor sodium after adrenalectomy.

Keratin14 mRNA expression in human pneumocytes during quiescence, repair and disease.

The lung alveoli slowly self-renew pneumocytes, but their facultative regeneration capacity is rapidly efficient after an injury, so fibrosis infrequently occurs. We recently observed Keratin 14 (KRT14) expression during diffuse alveolar damage (DAD), but not in controls. We wonder if KRT14 may be a marker of pneumocyte transition from quiescence to regeneration. Quantitative PCR and Western blot analyses highlighted the presence of KRT14 (mRNA and protein) only in human lung samples with DAD or interstitial lung disease (ILD). In the exponentially growing cell lines A549 and H441, the mRNA and protein levels of KRT14 peaked at day one after cell seeding and decreased at day two, opposite to what observed for the proliferation marker E2F1. The inverse relation of KRT14 versus E2F1 expression holds true also for other proliferative markers, such as cyclin E1 and cyclin D1. Of interest, we also found that E2F1 silencing caused cell cycle arrest and increased KRT14 expression, whilst E2F1 stimulation induced cell cycle progression and decreased KRT14. KRT14 also increased in proliferative pneumocytes (HPAEpiC) just before transdifferentiation. Overall, our results suggest that KRT14 is a viable biomarker of pneumocyte activation, and repair/regeneration. The involvement of KRT14 in regenerative process may suggest a novel pharmaceutical target to accelerate lung repair.

Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization.

Laser therapy, recently renamed as photobiomodulation, stands as a promising supportive treatment for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. Here we explored the anti-cancer effect of 3 laser protocols, set at the most commonly used wavelengths, in B16F10 melanoma and oral carcinogenesis mouse models. While laser light increased cell metabolism in cultured cells, the in vivo outcome was reduced tumor progression. This striking, unexpected result, was paralleled by the recruitment of immune cells, in particular T lymphocytes and dendritic cells, which secreted type I interferons. Laser light also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, an emerging strategy to control tumor progression. Collectively, these results set photobiomodulation as a safety procedure in oncological patients and open the way to its innovative use for cancer therapy.

MAD2 expression in oral squamous cell carcinoma and its relationship to tumor grade and proliferation.

BACKGROUND: Defects in the cell-cycle surveillance mechanism, called the spindle checkpoint, might contribute to the chromosomal instability observed in human cancers, including oral squamous cell carcinoma. MAD2 and BUBR1 are key components of the spindle checkpoint, whose role in oral carcinogenesis and clinical relevance still need to be elucidated. MATERIALS AND METHODS: We analyzed the expression of MAD2 in 49 cases of oral squamous cell carcinoma by immunohistochemistry and compared the findings with clinicopathological parameters, proliferative activity, BUBR1 expression and DNA ploidy. RESULTS: MAD2 was over-expressed in 18 (36.7%) cases. Tumors with over-expression of MAD2 were associated with the progression of histological grade from well to poor differentiation (p<0.001), the extent of lymph nodes involvement (PN) (p=0.0339) and Ki-67 labeling index (p<0.001). CONCLUSION: MAD2 may be involved in oral carcinogenesis and may represent an important prognostic factor associated with a more malignant phenotype of oral squamous cell carcinoma.