Retraction Note: Presence of viral spike protein and vaccinal spike protein in the blood serum of patients with long-COVID syndrome.

The article "Presence of viral spike protein and vaccinal spike protein in the blood serum of patients with long-COVID syndrome", by K. Dhuli, M.C. Medori, C. Micheletti, K. Donato, F. Fioretti, A. Calzoni, A. Praderio, M.G. De Angelis, G. Arabia, S. Cristoni, S. Nodari, M. Bertelli, published in Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 13-19-DOI: 10.26355/eurrev_202312_34685-PMID: 38112944 has been retracted by the Editor in Chief for the following reasons. Following some concerns raised on PubPeer, the Editor in Chief has started an investigation to assess the validity of the results. The outcome of the investigation revealed that the manuscript presented major flaws in the following: -       Unclear methodology and patient recruitment -       Discrepancies among data reported in the text and tables -       Unreliable results -       Undeclared conflict of interest Consequently, the Editor in Chief mistrusts the results presented and has decided to withdraw the article. The authors disagree with this retraction. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34685.

Linking pathogenic and likely pathogenic gene variants to long-COVID symptoms.

OBJECTIVE: Long-COVID is a clinical syndrome characterized by the presence of symptoms related to SARS-CoV-2 infection that persist for at least four weeks after recovery from COVID-19. Genetics have been proposed to play an important role in long-COVID syndrome onset. This study aimed to identify genetic pathogenetic and likely pathogenetic causative variants of Mendelian genetic diseases in patients with Long-COVID syndrome. Additionally, we aimed to establish an association between these genetic variants and the clinical symptoms manifested during long-COVID syndrome. PATIENTS AND METHODS: 95 patients affected by long-COVID syndrome were analyzed with a Next-Generation Sequencing (NGS) panel comprising 494 genes. The analyzed genes and the symptoms of the patients collected with an ad-hoc questionnaire were divided into four groups (cardiological, respiratory, immunological, and neurological). Finally, a statistical analysis comprising descriptive statistics, classification based on reported symptoms, and comparative analysis against a control group of healthy individuals was conducted. RESULTS: 12 patients resulted positive for genetic testing with an autosomal dominance (8) or autosomal recessive (4) inheritance, showing a higher prevalence of cardiovascular genetic diseases (9) in the analyzed cohort compared to the normal population. Moreover, the onset of the long-COVID syndrome and its cardiovascular manifestations was compliant with the onset reported in the literature for the identified genetic diseases, suggesting that COVID-19 could manifest late-onset genetic diseases associated with their appearance. Apart from the 12 positive patients, 57 were healthy carriers of genetic diseases. Analyzing the whole cohort, a statistical correlation between prevalent symptomatology and the gene class was established, suggesting an association between the genetic susceptibility of an individual and the possibility of developing specific long-COVID syndrome symptoms, especially cardiovascular symptoms. Furthermore, 17 genetic variants were identified in CFTR. Finally, we identified genetic variants in IFNAR2 and POLG, supporting their respective involvement in inflammation and mitochondria mechanisms, correlated with long-COVID syndrome according to literature data. CONCLUSIONS: This study proposed COVID-19 to act as a manifest of underlying late-onset genetic diseases Mendelian associated with carrier status. Moreover, according to our results, mutations in cardiological genes are more present in patients who show cardiological symptoms during the syndrome. This underscores the necessity for cardiological investigation and genetic screening in long-COVID patients to address existing or potential clinical implications.

Autoantibodies in patients with post-COVID syndrome: a possible link with severity?

OBJECTIVE: Coronavirus disease 2019 is an infectious disease associated with the respiratory system caused by the SARS-CoV-2 virus. Right now, an increasing number of patients with Post-COVID Syndrome show, without clear evidence of organ dysfunction, a plethora of severe symptoms, such as fatigue, pain, shortness of breath, cognitive impairment, and sleep disturbance. It has already been demonstrated that SARS-CoV-2 virus can disrupt the self-tolerance mechanism of the immune system, thus triggering autoimmune conditions. Several studies have recently documented the presence of autoantibodies in the sera of post-COVID patients, but until now, it is unclear whether the persistence of symptoms could be directly correlated with the presence of autoantibodies. PATIENTS AND METHODS: In this study, serum autoantibodies (AAbs) levels against four G protein-coupled receptors in 78 patients with post-COVID syndrome have been analyzed. The AAbs investigated are clustered in two groups: adrenergic receptors (α1 and ß2) and muscarinic acetylcholine receptors (M3 and M4). RESULTS: At least one or more AAbs were detected in 60.3% (47/78) of patients diagnosed with post-COVID syndrome, whereas 37.2% (29/78) of patients were positive for all receptors investigated. Interestingly, a strong correlation has been found between AAbs and pain intensity feeling by the patients measured by Visual Analogic Scale. A significant association was also obtained with insomnia and AABS-positive patients. CONCLUSIONS: The identification of AAbs and their correlation with pathological symptoms seriousness underly the possible role of AAbs as future therapeutic targets.

Serum proteomic profiling reveals potential inflammatory biomarkers in long-COVID patients: a comparative analysis with healthy controls.

OBJECTIVE: The highly transmissible severe acute respiratory syndrome-Coronavirus-2 was responsible for the 2020 COVID-19 pandemic. COVID-19 mostly affects the respiratory system; however, this infection also affects several other organs. In addition, the sequelae of this disease affect patients for several months after recovery, resulting in long-COVID syndrome. PATIENTS AND METHODS: In order to characterize the differences between healthy control individuals and long-COVID patients, proteomic profiling of the serum of both groups was performed by mass spectrometry. The obtained data were analyzed with multivariate and univariate statistical analyses. RESULTS: Initially, performing a partial latent square discriminant analysis (PLS-DA) made it possible to identify thirty-three proteins of interest, which were then subjected to a receiver operating characteristic (ROC) analysis. Four proteins were identified as potential stand-alone biomarkers: Sirtuin 1, Natriuretic Peptide B, Hemopexin, and Arachidonate 5-Lipoxygenase. Moreover, a multivariate ROC analysis identified a panel of biomarkers composed of Natriuretic Peptide B, Anterior Gradient 2 Protein, Adiponectin, Endothelin Converting Enzyme 1, Interferon Induced Transmembrane Protein 1, Mannose Binding Lectin 2, Prostaglandin-Endoperoxide Synthase 2, Pirin, Prostaglandin Reductase 1 and Cystatin C. CONCLUSIONS: The identified biomarkers are associated with inflammatory processes, corroborating literature evidence that long-COVID patients develop an inflammatory state that damages many tissues. Nevertheless, these data should be validated in a larger cohort.

Presence of viral spike protein and vaccinal spike protein in the blood serum of patients with long-COVID syndrome.

OBJECTIVE: COVID-19 patients experience, in 10-20% of the cases, a prolonged long-COVID syndrome, defined as the persistence of symptoms for at least two months after the infection. The underlying biological mechanisms of this syndrome remain poorly understood. Several hypotheses have been proposed, among which are the potential autoimmunity resulting from molecular mimicry between viral spike protein and human proteins, the reservoir and viral reproduction hypothesis, and the viral integration hypothesis. Although official data state that vaccinal spike protein is harmless and remains at the site of infection, several studies proposed spike protein toxicity and found it in blood circulation several months after the vaccination. To search for the presence of viral and vaccine spike protein in a cohort of long-COVID patients. PATIENTS AND METHODS: In this study, we employed a proteomic-based approach utilizing mass spectrometry to analyze the serum of 81 patients with long-COVID syndrome. Moreover, viral integration in patients' leukocytes was assessed with a preliminary study, without further investigation. RESULTS: We identified the presence of the viral spike protein in one patient after infection clearance and negativity of COVID-19 test and the vaccine spike protein in two patients two months after the vaccination. CONCLUSIONS: This study, in agreement with other published investigations, demonstrates that both natural and vaccine spike protein may still be present in long-COVID patients, thus supporting the existence of a possible mechanism that causes the persistence of spike protein in the human body for much longer than predicted by early studies. According to these results, all patients with long-COVID syndrome should be analyzed for the presence of vaccinal and viral spike protein.

The Role of Olive Tree Polyphenols In The Prevention of COVID-19: A Scoping Review Part 2.

Abstract: The recent COVID-19 pandemic caused by SARS-CoV-2 affected hundreds of millions of people and caused millions of deaths. There are few effective medications against SARS-CoV-2, and several studies attempted to make drugs based on natural components, such as olive leaves. Olive leaves are rich in polyphenolic compounds, which were proposed as a viable co-therapy supplement to treat and improve clinical symptoms in COVID-19 patients. Polyphenols have renown anti-inflammatory and multitarget antiviral effects on several virus families, which could be among the reasons of the beneficial effects of the Mediterranean diet against COVID-19. This scoping review is focused on the effect of olive tree polyphenols as a natural remedy to inhibit SARS-CoV-2, mainly discussing their influence on the process of viral entry into host cells by endocytosis.

The Role of Olive Tree Polyphenols in the Prevention of COVID-19: A Scoping Review, part 1.

Abstract: The global COVID-19 outbreak, started in December 2019, resulted in severe financial losses and extraordinary health crises. Finding a potent and secure medication candidate to treat SARS-CoV-2 infection and its symptoms is still an urgent global need. After reviewing previous studies, olive leaves, being rich in polyphenolic compounds (a large class of bioactive substances naturally found in plants), were proposed as a viable co-therapy supplement to treat and improve clinical symptoms in COVID-19 patients. It has long been known that olive tree polyphenols-such as oleuropein, hydroxytyrosol, verbascoside, as well as triterpenoids like maslinic, ursolic, and oleanolic acids-have anti-inflammatory and multitarget antiviral effects on several virus families, and they could be one of the reasons of the beneficial effects of the Mediterranean diet against COVID-19. Thus, olive tree poly-phenols were tested in silico and in vitro for preventing SARS-CoV-2 infection, claiming that they have beneficial effects. Nevertheless, there is still a small number of research studies on this topic. The aim of this scoping review is to provide more information and offer an opinion on the feasibility of using olive tree polyphenols as a springboard for the creation of innovative natural remedies against this viral illness, ultimately planning future relevant studies.

Proposal of a food supplement for the management of post-COVID syndrome.

A vast majority of COVID-19 patients experience fatigue, extreme tiredness and symptoms that persist beyond the active phase of the disease. This condition is called post-COVID syndrome. The mechanisms by which the virus causes prolonged illness are still unclear. The aim of this review is to gather information regarding post-COVID syndrome so as to highlight its etiological basis and the nutritional regimes and supplements that can mitigate, alleviate or relieve the associated chronic fatigue, gastrointestinal disorders and continuing inflammatory reactions. Naturally-occurring food supplements, such as acetyl L-carnitine, hydroxytyrosol and vitamins B, C and D hold significant promise in the management of post-COVID syndrome. In this pilot observational study, we evaluated the effect of a food supplement containing hydroxytyrosol, acetyl L-carnitine and vitamins B, C and D in improving perceived fatigue in patients who recovered from COVID-19 but had post-COVID syndrome characterized by chronic fatigue. The results suggest that the food supplement could proceed to clinical trials of its efficacy in aiding the recovery of patients with long COVID.

An unusual thoracic localizations of Erdheim- Chester disease: A case report.

Erdheim- Chester disease is a rare non- Langerhans cell histiocytosis that usually involves the bones, heart, central nervous system, retroperitoneum, eyes, kidneys, skin and adrenals. Lungs are affected in up to one-half cases; at CT scan various patterns are described: interstitial disease, consolidations, micronodules and microcysts, with or without pleural involvement. We presented a case of a 59 year-old man with unusual intrathoracic manifestation of Erdheim- Chester disease. Singularities of our report are the lonely thoracic involvement at the onset of the disease and a histiocytic lesion in the posterior mediastinum.

Revising the role of the androgen receptor in breast cancer.

Breast cancer (BC) is traditionally viewed as an oestrogen-dependent disease in which the androgen receptor (AR) is inhibitory, counteracting the oncogenic activity of oestrogen receptor α (ERα (ESR1)). Most probably as a result of this crosstalk, the AR has prognostic value in ER-positive disease, with AR positivity reported to correlate with a better prognosis. Activation of the AR pathway has been previously used as a therapeutic strategy to treat BC, but its usage declined following the introduction of the anti-oestrogen tamoxifen. More recently, it has been demonstrated that a subset of triple-negative BCs (molecular apocrine) are dependent upon androgen signalling for growth and therapies that inhibit androgen signalling, currently used for the treatment of prostate cancer, e.g. the antiandrogen bicalutamide and the CYP17 inhibitor abiraterone acetate are undergoing clinical trials to investigate their efficacy in this BC subtype. This review summarises the current knowledge of AR activity in BC.

Nano-odontology: nanostructured assemblies for endodontic regeneration.

The vitality of the pulp is so fundamental to the functional life of the tooth that new strategies are required to avoid the removal of the whole pulp following irreversible pulpitis and to regenerate the lost endodontic tissues. Nano-odontology would provide suitable solutions for pulp tissue conservative and regenerative approaches. In our group, we have shown that when covalently coupled to Poly-Glutamic Acid (PGA) the incorporation of an anti-inflammatory hormone (melanocortin, a-MSH) into the multilayered films Poly-L-Lysine (PLL)/PGA increases the anti-inflammatory reaction of pulp fibroblasts and macrophages stimulated by LPS (Lipo-Polysaccharides). Recently, usual linear PLL polymers have been chemically grafted for making new Dendrigraft polymers (DGLG4) whose higher branching ratios can give useful properties. The objective is to use nanostructured assemblies containing DGLG4 and PGA-alpha-MSH to design a new nanomaterial. These nanostructured assemblies (DGLG4-PGA-alpha-MSH)n constitute a thick reservoir of the anti-inflammatory peptide and promote adhesion and proliferation of pulp fibroblast on the biomaterial surface. These nanostructured films could be adapted for an endodontic regeneration application to target pulp connective tissue regeneration. Firstly, the crucial reduction of inflammation could be helpful by using PGA-alpha-MSH and secondly the initiation of the regeneration of the connective tissue will be promoted by the whole nanostructured film of which allows pulp cells colonisation.

[The new materials in prolapse surgery and incontinence]. / I nuovi materiali nella chirurgia del prolasso e dell'incontinenza.

In line with the results of general surgeons, who revolutionised the surgical approach and the success rate of ventral hernia repair using synthetic mesh, urologists and gynaecologists recently moved towards the use of prosthesis to augment the native tissues. The rationale was based on the relatively high failure rates of the traditional anterior vaginal compartment repair and the recognition that the native tissue may no longer assume the position, strength or functionality by simple re-approximation. Actually the plethora of mesh or graft material, ranging from absorbable (synthetic and biological) to non-absorbable materials, indicates how uncertain we are about the best management. The surgical results are variable on the basis of 1) the material used (synthetic or biological, absorbable or not absorbable); 2) the position of the mesh (incorporated in the suture, overlay the suture, below or under the fascia); 3) the tension adopted. Major problems concern the complications related to the use of the meshes in urogynaecological surgery and the final message is that surgeons may want to consider adopting use of graft techniques to improve surgical results with care given to carefully monitor complications.

The management of pelvic organ prolapse: a review.

The increase of the prevalence of pelvic organ prolapse (POP) and urinary incontinence (UI), associated to changes in longevity, population demographics, and lifestyle expectation, is leading to a different set of urogynecological surgical challenges for 21st century women The objective of this review is to determine the characteristics and the effects of the different surgical technique in the management of POP. Here, we reviewed traditional techniques as well as we are going to take in consideration the introduction of several new procedures involving the use of different meshes or grafts, with or without introducer kits. Finally the laparoscopic approaches and the rapidly evolving robotic surgery will be discussed. Waiting for studies with high level of evidence, due to the plethora of techniques, mesh or graft material, absorbable (synthetic and biological) and non-absorbable, at present, there seems to be no final evidences about the best management.

Erectile dysfunction and NO: variations of NO penile blood levels before and after sildenafil treatment.

Erectile dysfunctions are not uncommon, especially in patients suffering from metabolic syndrome and from a number of circulatory and psychiatric problems. cGMP diesterase inhibitors, such as sildenafil, have proven to be beneficial in the treatment of many such conditions. Our patients, all of them complaining of erectile dysfunction, were treated with sildenafil (50 mg, thrice a week for 6 weeks). All patients reported beneficial effects and were not clinically distinguishable (interview and Doppler scores). We sampled blood for systemic circulation (cubital vein) and from penis (corpora cavernosa) before and after prolonged sildenafil treatment, and measured nitrate (+nitrite) levels in plasma and in red blood cells (RBCs). Hemoglobin is a powerful catalyst of NO oxidation to nitrate, and we thought that nitrate in RBC might be a more sensitive parameter than plasma nitrate. We found that the ratio of penile vs systemic blood plasma nitrate was similar in all patients before or after sildenafil treatment. On the other hand, the same parameter measured in RBC showed that, at the beginning of treatment, patients could be divided into two groups: one with a high ratio and the other with a low ratio. Therefore, clinically similar patients could be biochemically divided into two populations. The difference disappeared after treatment, thus hinting at a curative effect of the drug. The mechanisms underlying this behavior are still unknown and the clinical implication of two populations that can be distinguished by RBC nitrate is yet to be evaluated.

The role of matrix metalloproteinases (MMPs) in human caries.

The objective of this review is to summarize our understanding of the role of host matrix metalloproteinases (MMPs) in the caries process and to discuss new therapeutic avenues. MMPs hydrolyze components of the extracellular matrix and play a central role in many biological and pathological processes. MMPs have been suggested to play an important role in the destruction of dentin organic matrix following demineralization by bacterial acids and, therefore, in the control or progression of carious decay. Host-derived MMPs can originate both from saliva and from dentin. They may be activated by an acidic pH brought about by lactate release from cariogenic bacteria. Once activated, they are able to digest demineralized dentin matrix after pH neutralization by salivary buffers. Furthermore, the degradation of SIBLINGs (Small Integrin-binding Ligand N-linked Glycoproteins) by the caries process may potentially enhance the release of MMPs and their activation. This review also explores the different available MMP inhibitors, natural or synthetic, and suggests that MMP inhibition by several inhibitors, particularly by natural substances, could provide a potential therapeutic pathway to limit caries progression in dentin.

Tumor necrosis factor alpha (TNFalpha) and its soluble receptor p75 (sTNF-R p75) in familial combined hyperlipidemia (FCHL).

BACKGROUND AND AIM: Familial combined hyperlipidemia (FCHL) is a genetic disorder of lipid metabolism associated with insulin resistance and abnormalities in fatty acid metabolism whose underlying mechanisms are largely unknown. Perturbations in the TNFalpha/TNF-R pathway may play a role in these abnormalities. METHODS AND RESULTS: We determined plasma levels of TNFalpha and sTNF-R p75 in 85 FCHL patients (TC 245+/-45 mg/dl; TG 260+/-148 mg/dl; apoB 148+/-37 mg/dl) and in 29 age- and sex-matched normolipemic relatives (NL) (TC 187+/-22.8 mg/dl; TG 115+/-37 mg/dl; apoB 106+/-16 mg/dl). Thirty-four normolipemic subjects (TC 180+/-34 mg/dl; TG 107+/-42 mg/dl; apoB 95+/-22 mg/dl) were also included as unrelated controls (NC). Plasma free fatty acids (NEFA) were also measured and insulin sensitivity was evaluated by HOMA. Levels of sTNF-R p75 were significantly reduced in FCHL compared to NL (2.30+/-0.55 ng/ml vs. 2.64+/-0.88 ng/ml, p<0.05) but not compared to NC (2.35+/-0.68 ng/ml). HOMA values were comparable in all groups and did not show any relation with plasma levels of sTNF-R p75. Logistic analysis demonstrated that a low concentration of sTNF-R p75 was an independent predictor of the affected status within FCHL families, but this role was no longer evident when FCHL patients were compared to NC. In FCHL, age (p<0.001) was positively, and TG (p=0.029) and HDL-C (p=0.025) were negatively correlated with plasma concentrations of sTNF-R p75. In the other groups, age (in NL) and non-HDL-C (in NC) were significantly correlated with sTNF-R p75. CONCLUSIONS: Although our data do not support a causative role of TNFalpha/TNF-R alterations in FCHL, they confirm that variation in TNF-R shedding may influence lipid phenotypic expression in FCHL families.

Sex differences in colorectal cancer mortality in Europe, 1955-1996.

Colorectal cancer is the leading cancer in non-smokers in Western countries, and over the last decades its trends have been generally more favourable for women than for men. Possible explanations of the sex differentials in colorectal cancer relate to different exposure to exogenous hormones and to other risk factors including diet, physical activity and alcohol drinking. The objective of this investigation was to systematically analyse the trends in colorectal cancer mortality sex ratios in major European countries over the last four decades. Trends in death certification rates from colorectal cancer over the period 1955-1996 were analysed for 20 European countries (excluding the former Soviet Union and a few of the smaller countries). In all countries, the mortality sex ratios (M/F) were around or slightly above unity in the 1950s, and systematically increased to approach 1.5 in the 1990s. The extent of the rises varied across countries, ranging between + 0.8% in Germany, + 9.7% in Sweden, and + 12.1% in Denmark (the lowest increases) to + 65.3% in Spain, + 56.2% in Portugal, and + 50.4% in Hungary (the highest ones). Mortality sex ratios in Europe show more favourable trends for females, which may be attributable, in part, to the introduction of exogenous hormones in the late 1950s and 1960s, and, in part, to differential sex exposure to major environmental risk factors.

Menopause and risk of non-fatal acute myocardial infarction: an Italian case-control study and a review of the literature.

The relationship between menopause and non-fatal acute myocardial infarction (AMI) was considered by analysing data from a case-control study conducted in Italy between 1983 and 1992. Cases were 429 women, below age 75 years, with a first episode of non-fatal AMI, admitted to 30 coronary care units; controls were 863 women admitted to the same network of hospitals for acute diseases other than cardiovascular, neoplastic, or hormone-related. Postmenopausal women were not at higher risk of AMI than pre/perimenopausal women, after adjustment for age and other selected covariates [multivariate odds ratio (OR) 0.99]. With reference to age at menopause, compared with women reporting menopause when <45 years, the multivariate OR were 1.54 for those aged 45-49 at menopause, 1.36 for those aged 50-52 years, and 0.97 for those aged >/=53, in the absence of any trend in risk. No meaningful relationship emerged with time since menopause (OR 0.85 for <10 years since menopause). The results were similar in women aged <60 and >/=60 years at AMI. Although the present study does not support a substantial relationship between menopause and non-fatal AMI, the overall epidemiological evidence is compatible with a moderate association.

Menstrual and reproductive factors and risk of soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a heterogeneous group of neoplasms whose etiology remains largely undefined. A role for female hormones in the development of STS has been suggested. To investigate this possibility, the authors analyzed data from a hospital-based case-control study conducted in Northern Italy between 1983 and 1998. METHODS: Cases were 104 women aged < 79 years with incident STS who were admitted to the cancer institutes and major teaching and general hospitals. Controls were 505 women admitted to the same network of hospitals for acute, nonneoplastic, nongynecologic, and nonimmune-related conditions. RESULTS: The multivariate odds ratio (OR) for women aged >/= 15 years compared with those aged < 12 years at menarche was 1.94 (95% confidence intervals [95% CI], 0.80-4.74). No association with STS risk was observed for menstrual cycle pattern, age at menopause, parity, and abortions. Late age at first pregnancy and birth were found to be related to an increased risk of STS, with an OR of 3.16 (95% CI, 0. 96-10.44) and 2.79 (95%% CI, 0.79-9.90) for women aged >/= 30 years at first pregnancy and birth compared with those aged < 20 years. The trend in risk was significant for age at first pregnancy. No relation with the risk of STS emerged for age at last birth and time since first or last birth. CONCLUSIONS: The risk of STS was found to be weakly related to late age at first pregnancy or birth, but not to other menstrual and reproductive factors.