The recommended lifetime immunization schedule from the board of vaccination calendar for life in Italy: A continuing example of impact on public health policies.

The Vaccination Calendar for Life is an alliance of scientific and professional societies of public health physicians, paediatricians and general practitioners in Italy which provides a periodical update on the ideal, scientifically driven vaccination calendar throughout lifetime. Since 2012, the Lifetime Immunization Schedule has represented a benchmark for Regional and National Authorities to set up the updated list of vaccines provided actively and free of charge to infants, children, adolescents, adults and the elderly by inclusion in the Triennial National Vaccination Plan (TNVP), and in the Essential Levels of Care (LEA). The impact of the different editions of the Lifetime Immunization Schedule on the TNVP was deep, representing the inspiring source for the present vaccination policy. The 2019 edition called for more attention to pregnant women immunization; risk groups vaccination; uniform high coverage with the MMRV vaccine; extension of Meningococcal B vaccination also at adolescent age; use of quadrivalent conjugate meningococcal vaccine also at 1 year of life; progressive decrease of the age of free-of-charge offer of influenza to ≥ 60 and then to ≥ 50 year-old population; implementation of flu immunization ages 6 months-6 years; HPV vaccination also offered to 25-year old women at the time of the first screening (gender neutral immunization already offered); sequential PCV13-PPV23 pneumococcal vaccination in 65 year-old subjects; increased coverage with rotavirus vaccine in infants and zoster vaccine in the elderly.

Maintain and increase vaccination coverage in children, adolescents, adults and elderly people: Let's avoid adding epidemics to the pandemic: Appeal from the Board of the Vaccination Calendar for Life in Italy: Maintain and increase coverage also by re-organizing vaccination services and reassuring the population.

The Board of the Vaccination Calendar for Life (Bonanni et al., 2014, 2017) [1,2]), a coalition of four major scientific and professional societies of public health physicians, pediatricians and general practitioners in Italy, made an appeal to health authorities in order to sustain vaccination in COVID-19 times. The five pillars to maintain and increase vaccination coverage at all ages are described as follows: 1) Guarantee paediatric vaccination coverage to all newborns and paediatric boosters and adolescent immunizations, not interrupting active calls and scheduled sessions. 2) Re-organise the way paediatric and adolescent vaccinations are offered. 3) Set-up recovery programs for vaccinations not carried out after the start of the COVID-19 emergency. 4) Provide the preparation of tenders for the supply of flu vaccines with suitable quantities to increase coverage in all Regions and Autonomous Provinces with extreme urgency. 5) Prepare plans to increase coverage for influenza, pneumococcal, tetanus diphtheria and shingles. The Board of the Calendar for Life appeals to the National and Local Health Authorities for a strong and coordinated commitment in favor of the widest offer and acceptance of vaccinations, whose vital importance for collective health is now even more evident to all, in order to avoid that delays in the necessary initiatives should add damage from other epidemics to those suffered by our population due to the COVID-19 pandemic.

SARS-CoV-2 infection: NLRP3 inflammasome as plausible target to prevent cardiopulmonary complications?

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.

COVID-19: is it just a lung disease? A case-based review.

Due to its extreme virulence, COVID-19 virus has rapidly spread, developing a severe pandemic. SARS-COV-2 mostly affected the respiratory tract, causing a severe acute lung failure. Although the infection of airways, COVID-19 can be associated with chronic and systemic damages still not so much known. The purpose of this research is to collect recent evidence in literature about systemic diseases caused by COVID-19. The format of the present article has features of a systematic case-based review (level of evidence), and it is structured as a case series report (patients of our COVID-19 Medicine Ward have been selected as cases). Data for this review have been selected systematically, taking evidence only from indexed journals and databases: PubMed, Scopus, MEDLINE, and Cochrane systems. Papers chosen included systematic reviews, case series, clinical cases, meta-analysis studies, and RCTs. We start collecting studies since 2003. The main keywords used were "COVID-19" "OR" "SARS" "OR" "SARS - COV 2" "AND" "systemic disease" / "nephropathy" / "cardiac pathology" / "central nervous system." Clinical cases belong to our COVID-19 Medicine Ward. One of the most severe COVID-19 clinical presentations includes cardiovascular problems, like myocarditis, pericarditis, and acute hearth failure. Cytokine release syndrome caused by COVID-19 develops severe acute kidney failure. It is still unknown the way coronavirus damages the liver, brain, and reproductive system. Considering the majority of the new studies about this pathology, it issues that COVID-19 is considered to be a multi-organ disease.

From less to maximally invasiveness in cervical spine surgery: A "nightmare" case who deserve consideration.

INTRODUCTION: Multilevel cervical myelopathy without surgical treatment is generally poor in the neurological deficit without surgical decompression. The two main surgical strategies used for the treatment of multilevel cervical myelopathy are anterior decompression via anterior corpectomy or posterior decompression via laminctomy/laminoplasty. PRESENTATION OF CASE: We present the case of a 62 year-old lady, harboring rheumatoid artritis (RA) with gait disturbances, pain, and weakness in both arms. A C5 and C6 somatectomy, C4-C7 discectomy and, instrumentation and fusion with telescopic distractor "piston like", anterior plate and expandable screws were performed. Two days later the patient complained dysfagia, and a cervical X-ray showed hardware dislocation. So a C4 somatectomy, telescopic extension of the construct up to C3 with expandible screws was performed. After one week the patient complained again soft dysfagia. New cervical X-ray showed the pull out of the cranial screws (C3). So the third surgery "one stage combined" an anterior decompression with fusion along with posterior instrumentation, and fusion was performed. DISCUSSION: There is a considerable controversy over which surgical approach will receive the best clinical outcome for the minimum cost in the compressive cervical myelopathy. However, the most important factors in patient selection for a particular procedure are the clinical symptoms and the radiographic alignment of the spine. the goals of surgery for cervical multilevel stenosis include the restoration of height, alignment, and stability. CONCLUSION: We stress the importance of a careful patients selection, and invocated still the importance for 360° cervical fixation.

Indocyanine green video-angiography in neurosurgery: a glance beyond vascular applications.

OBJECTIVE: Indocyanine green video angiography (ICG-VA) is a non invasive, easy to use and a very useful tool for various neurosurgical procedures. Initially introduced in vascular neurosurgery since 2003, it's applications have broadened over time, both in vascular applications and in other neurosurgical fields. The objective of our study is to review all published literature about ICG-VA, cataloguing its different applications. METHODS: A systematic review of all pertinent literature articles published from January 2003 to May 2014 using Pubmed access was performed using pertinent keywords; cross check of references of selected articles was performed in order to complete bibliographical research. Results of research were grouped by pathology. RESULTS AND CONCLUSIONS: The paper systematically analyses ICG-VA different applications in neurosurgery, from vascular neurosurgery to tumor resection and endoscopic applications, focusing on reported advantages and disadvantages, and discussing future perspectives.

Absence of interference of serum IgGs from patients with breast cancer and thyroid autoimmunity on the function of human iodide symporter gene stably transfected in CHO cells.

The cause of the association between breast cancer (BC) and thyroid autoimmunity is still unknown. Na+/I- symporter (NIS) is highly expressed in BC cells, and previous studies demonstrated that iodine content in BC is lower than in remote normal breast tissue, suggesting a disorder of iodide uptake in BC. In this study, we evaluated the presence of putative serum autoantibodies able to block the function of NIS in BC patients with thyroid autoimmunity. IgGs were obtained from: a) 11 patients with BC and high antithyroglobulin (TgAb) and antithyroperoxidase (TPOAb) autoantibodies serum concentration; b) 34 patients with Hashimoto's thyroiditis (HT) (1 was euthyroid, 4 had subclinical hypothyroidism and 29 were overtly hypothyroid); c) 15 control subjects. The biological activity of NIS was studied using a chinese hamster ovary (CHO) cell line stably expressing NIS (NIS-CHO). The course of iodide accumulation in NIS-CHO was studied after addition of Na125 I in culture medium. The accumulation of iodide linearly increased between 2 and 10 min, reaching a plateau at 45 min. The preincubation of NIS-CHO with IgGs purified from sera of BC with the highest levels of TPOAb and TgAb caused an inhibition of iodine uptake of no more than 5%. Similar results were obtained using IgGs purified from patients with HT and control subjects. Our data showed no interference of autoantibodies on iodine uptake in patients with BC and thyroid autoimmunity and the very low percentage of inhibition of iodine uptake cannot explain the lower content of iodine in BC tissue.

Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation.

The apoptotic response and the level of expression of p53 and of three genes transcriptionally activated by p53 (Mdm2, p21 and bax) were investigated in UV-sensitive cells from patients with xeroderma pigmentosum (XP) or Cockayne syndrome (CS). These disorders are due to different genetic defects affecting transcription-coupled repair (TCR) and/or global genome repair (GGR), the nucleotide excision repair subpathways which remove UV-induced lesions from the transcribed strand of active genes or from the rest of the genome, respectively. After 20 J/m2 UV light, normal and GGR-defective XP-C fibroblasts showed rapid increase in p53, late induction of Mdm2 and no evidence of apoptosis even 96 h after irradiation. In contrast, in XP-A (defective in GGR and TCR), CS-A and CS-B (defective only in TCR) fibroblasts, the p53 increase was not followed by Mdm2 induction and the persistence of high levels of p53, due to the lack of its degradation by Mdm2, was associated with the appearance of apoptosis. Besides indicating that the persistence of DNA damage in the transcribed strand of active genes leads to apoptosis, these findings provide the first evidence that the lack of activation of Mdm2 plays a key role in the cascade of events leading to apoptosis. Oncogene (2000).

Immunization with anti-neutrophil cytoplasmic antibody (ANCA) induces the production of mouse ANCA and perivascular lymphocyte infiltration.

Wegener's granulomatosis (WG) is a granulomatous necrotizing vasculitis associated with the presence of ANCA, predominantly directed against proteinase 3 (PR3). The titres of ANCA correlate with disease activity and titre increases may precede disease exacerbations. Previously, we have shown that it is possible to induce autoimmune disease (systemic lupus erythematosus (SLE) and anti-phospholipid syndrome) in naive mice following active immunization with human autoantibodies, namely anti-DNA and anti-cardiolipin, respectively. The mice developed first anti-autoantibodies and, after about 4 months anti-anti-autoantibodies (Ab3), simulating auto-antibodies (Ab1) in their binding activities, and their presence was associated with the development of disease manifestations, characteristic of the human disease. So far, there is no good animal model for WG. In the current study we have immunized mice with human ANCA with the aim of inducing experimental WG. In two separate studies 30 mice were immunized in their footpads with autoantigen-purified IgG fraction (ANCA) from the sera of two patients with untreated WG, emulsified in Freund's complete adjuvant, followed 3 weeks later by ANCA injection in PBS. In the first experiment mice immunized with ANCA developed sterile microabscesses in the lungs after 8 months, and died after 8-15 months. In the second experiment, mice immunized with ANCA developed after 4 months mouse ANCA, with specificity both to PR3 and to myeloperoxidase, as well as anti-endothelial autoantibodies (AECA), as shown by radioimmunoprecipitation. Pathologically, the immunized mice developed proteinuria but not haematuria, and histological sections of the lungs demonstrated mononuclear perivascular infiltration, while diffuse granular deposition of immunoglobulins was noted in the kidneys. Our results point to a pathogenic role of ANCA in WG, and confirm the importance of the idiotypic network in the etiopathogenesis of autoimmune conditions.

Different vimentin expression in two clones derived from a human colocarcinoma cell line (LoVo) showing different sensitivity to doxorubicin.

We selected two clones, isolated from the human colocarcinoma cell line LoVo, showing a sensitivity to doxorubicin similar to (LoVo clone 5) or three times lower than (LoVo clone 7) the parental cell line. Since vimentin was atypically expressed in a human breast carcinoma cell line made resistant to doxorubicin, we looked at vimentin expression in these two clones with spontaneously different sensitivity to the drug. For comparison we used the parental cell line LoVo WT and LoVo/DX made resistant pharmacologically. mRNA for vimentin was undetectable by Northern blot analysis in LoVo WT and in LoVo clone 5, while expression of this gene was high in LoVo clone 7 and in LoVo/DX. This increase in mRNA levels was not related to an amplification of DNA, as suggested by Southern blot analysis. Immunofluorescence and immunocytochemistry findings confirmed, at protein level, the mRNA data. In LoVo clones 5 and 7, there were respectively 8.6% and 71% vimentin-positive cells, although the two clones showed similar expression of multidrug resistance gene 1 (mdr-1) and accumulated intracellular doxorubicin at similar levels. Similarly, drug efflux was the same for both clones. Our results show for the first time that cells resistant to doxorubicin express vimentin independently of the mdr glycoprotein. However when cells from clone 5 were transfected with human vimentin cDNA, they did not become resistant, indicating that vimentin can be considered as a marker of resistance in these cells but does not give rise to a resistant phenotype by itself.

Clustering of vitronectin and RGD peptides on microspheres leads to engagement of integrins on the luminal aspect of endothelial cell membrane.

In previous work (Conforti et al, Blood 80:437, 1992), we have shown that integrins in endothelial cells (EC) are not polarized to the basal cell membrane, but are also exposed on the apical cell surface, in contact with blood. Therefore, endothelial integrins might be available for binding circulating plasma proteins. However soluble plasma vitronectin (vn) bound very poorly to EC apical surface and this interaction was unaffected by Arg-Gly-Asp (RGD) peptides or an anti-alpha v beta 3 serum. In contrast, beads (diameter, 4.5 microns) coupled with plasma vn associated to EC apical surface in a time- and concentration-dependent way. Addition of antibodies directed to vn, alpha v beta 3, and RGD-containing peptides blocked the interaction of vn beads with EC. In contrast, heparin and antibodies directed to alpha v beta 5 and beta 1 integrin chain had no effect. Beads coupled with Gly-Arg-Gly-Asp-Ser-Pro bound to the EC surface, but not those coupled with Gly-Arg-Gly-Glu-Ser-Pro. This interaction was blocked by alpha v beta 3 antibodies and RGD peptides, but not by alpha v beta 5 antibody. Overall, these results indicate that luminal alpha v beta 3 retains its binding capacity for surface-linked vn and RGD-containing ligands, but binding is observed only when the ligand is offered in a clustered, multivalent form. We propose that when vn or RGD-containing proteins are bound to circulating cells, they can act as bridging molecules by promoting adhesion of the cells to the endothelium via apical integrins.

Characterization of the endothelial surface proteins recognized by anti-endothelial antibodies in primary and secondary autoimmune vasculitis.

The antigenic structures recognized by anti-endothelial cell antibodies (AECA) in sera from 10 Wegener's granulomatosis (WG) and 12 systemic lupus erythematosus (SLE) patients with signs of vasculitis were characterized by immunoprecipitation of selectively radiolabeled surface membrane proteins from human umbilical vein endothelial cells. Electrophoretic analysis of the immunoprecipitated proteins revealed reactivities against endothelial antigens ranging in size from 200 to 25 kDa. AECA antigens were not cell specific, since the same sera also reacted, at least in part, with radiolabeled human fibroblast surface proteins. The majority of WG patients displayed a constant precipitation pattern of five proteins (180, 155, 125, 68, and 25 kDa). On the contrary, AECA from SLE sera reacted with a more heterogeneous series of endothelial proteins. A group of four proteins, however, was also found in the majority of SLE sera: 200, 180, 155, and 25 kDa. In addition, some endothelial antigens were immunoprecipitated only by WG (125 kDa) or by SLE sera (200 kDa), suggesting a different endothelial reactivity in different vasculitic processes. The reaction did not involve intracellular proteins as demonstrated by the lack of reactivity of SLE sera negative for AECA but positive for anti-cytoplasmic or anti-nuclear antibodies. These data confirming that AECA recognize surface endothelial determinants further support a potential pathogenetic role for these antibodies in autoimmune vasculitis.

Cell-surface plasminogen activation causes a retraction of in vitro cultured human umbilical vein endothelial cell monolayer.

Vascular endothelium forms a dynamic interface between blood and underlying tissues. Endothelial monolayer integrity is required for controlled vascular permeability and to preclude exposure of subendothelial cell matrix to circulating cells. Recent studies have established that cultured human umbilical vein endothelial cells (ECs) express receptors for plasminogen (plg) and urokinase-like plasminogen activator (uPA). In the present study, we provide evidence that in EC, uPA receptor is present in focal contacts and at cell-cell contact sites. In these cells, addition of plg and uPA to confluent EC generates a retraction of the monolayer that is evidenced by loss of cell-cell contacts and increase in monolayer permeability. The phenomenon is reversible even after 6 hours of plg-uPA treatment. Inhibition of plg-uPA effect is obtained with plasmin inhibitors, as well as reagents that block binding of uPA or plg to the cell surface. The retractive effect of plg-uPA is concomitant to surface activation of plasminogen and to the loss of cell-cell activation of plg can induce EC retraction, possibly by causing proteolysis at specific cell-cell contacts and cell-matrix sites. This process may be important in mediating the passage of metastatic tumor cells through an intact EC monolayer as well as in regulating contacts between circulating cells and endothelium.

Left ventricular remodelling in the year after myocardial infarction: an echocardiographic, haemodynamic, and radionuclide angiographic study.

BACKGROUND: The factors that influence infarct expansion early after myocardial infarction have been identified; however, there is less information about late-phase left ventricular enlargement. This study was designed to identify the clinical, haemodynamic, echocardiographic, and radionuclide angiographic criteria that predict the progress of left ventricular dilation after discharge for a first-anterior myocardial infarction. METHODS: Sixty-seven patients with first Q-wave acute anterior myocardial infarction not treated with thrombolytic agents underwent baseline echocardiographic, haemodynamic, and radionuclide angiographic evaluation 4-7 days after the onset of symptoms. The echocardiographic and radionuclide evaluations were repeated after 1 year in the 55 patients who completed the follow-up. By multivariate stepwise linear regression analysis, left ventricular end-diastolic volume after 1 year and change from baseline were modelled as a function of baseline left ventricular end-diastolic volume and other potential predictors. RESULTS: A model including left ventricular end-diastolic pressure, global wall motion score, baseline left ventricular end-diastolic volume, and a Thrombolysis in Myocardial Infarction (TIMI) score of 0-1 was able to predict 84% of the left ventricular end-diastolic volume at the follow-up; a TIMI score of 0-1, the transverse end-diastolic diameter, global wall motion score, and the number of coronary vessels with 70% stenosis accounted for 81% of the variation in left ventricular end-diastolic volume from baseline, while the transverse end-diastolic diameter was inversely related to this parameter. CONCLUSIONS: The results of this study demonstrate that after an anterior myocardial infarction, the patency of the infarct-related artery is the major determinant of late left ventricular dilation, while left ventricular end-diastolic pressure influences early left ventricular dilation and baseline end-diastolic volume. Therefore, to improve left ventricular remodelling, it appears necessary to increase the patency of the infarct-related artery and improve the diastolic loading of the left ventricle at an early stage in the infarction. The inverse relationship between baseline left ventricular transverse diameter and the change in left ventricular volume after discharge indicates that the higher the baseline left ventricular volume, the less it changed during the follow-up. The global wall motion score appears to be a non-invasive parameter that is useful for identifying patients with a high risk of progressive left ventricular dilation.

Alpha v beta 5 integrin is localized at focal contacts by HT-1080 fibrosarcoma cells and human skin fibroblasts attached to vitronectin.

In this study we characterized alpha v beta 5 integrin on HT-1080 fibrosarcoma cells. First, alpha v beta 5 integrin was immunoprecipitated by 125I-surface labeled HT-1080 cells using a polyclonal antibody specific for beta 5 subunit (cytoplasmic domain). A heterodimer consisting of a beta 5-chain running at 100 kD (reduced) and 90 kD (non-reduced) associated with an alpha-chain 145 kD (non-reduced) and 125 kD (reduced) was obtained by SDS-PAGE and autoradiography. By double-immunofluorescence labeling, we then investigated alpha v beta 5 distribution on HT-1080 cells. Upon staining with anti-beta 5 subunit antibody, alpha v beta 5 was detected in focal contacts on cells attached to vitronectin (vn), co-localizing with vinculin at the end of actin filaments. Comparative analysis of alpha v beta 5 and alpha v beta 3 showed that both receptors can occupy the same focal contact, although on the same cell mostly they are clustered in independent focal contacts. Focal distribution of alpha v beta 5 was also found on normal human fibroblasts attached to vn, suggesting that this is not a specific feature of HT-1080 cells. Finally, we investigated the role of alpha v beta 5 and alpha v beta 3 integrins in mediating HT-1080 cell adhesion to vn. Inhibition studies using antibodies with function-blocking activity to alpha v beta 5 and alpha v beta 3 suggest a primary role of alpha v beta 5 to support cell adhesion, with a weak contribute of alpha v beta 3. Their activity can be modulated by divalent cations. Our results provide the first evidence of focal distribution of alpha v beta 5 integrin on cells attached to vn.

[Transrectal echography in the assessment of anastomosis and local recurrence after prior resection]. / L'ecografia transrettale nella valutazione dell'anastomosi e delle recidive locali dopo resezione anteriore.

The value of rectal endosonography was investigated in the follow-up of the patients submitted to anterior resection for rectal cancer. Rectal endosonography was performed on 42 patients who had been operated on two months to five years before; all patients were monitored according to a carefully planned follow-up schedule including clinical and instrumental examinations and laboratory tests. Sixteen patients had altered clinical and laboratory data; 26 were completely asymptomatic. In the latter group, no signs of local recurrences were found, while in 4 cases the rectal wall appeared homogeneously thickened and hypoechoic: this pattern was due to postoperative or post-irradiation hyperemic-edematous phenomena. In 14 of 16 symptomatic patients, a mass was detected--in 9 of them inhomogeneous and hypoechoic and developing mainly in the perirectal perianastomotic tissue and in 5 limited to the rectal wall, in the anastomotic area. In the last 2 cases, no lesions were found. Both the manual and the stapler anastomoses were always demonstrated, which exhibited different US patterns. US findings were compared with histologic results or were clinically checked in the subsequent follow-up. To conclude, rectal endosonography proved to be useful in the postoperative follow-up of this kind of patients even though it did not allow the differential diagnosis between fibrosis and local recurrence.

Human endothelial cells express integrin receptors on the luminal aspect of their membrane.

Endothelial cells (EC) form a dynamic interface between blood and the rest of the body. EC surface properties promoting adhesion of reactive plasma proteins and/or circulating cells might be of pivotal importance for the homeostasis of blood and tissues. EC express multiple integrin receptors that promote their attachment to the subendothelial matrix proteins. Among these receptors, alpha v beta 3 is of particular relevance on EC, since it is abundantly expressed and can bind many different matrix and plasma proteins. It is still unknown whether integrin receptors are selectively located to the basal side of EC membrane or may also be exposed on the cell surface in contact with blood. This issue was addressed using different experimental approaches. First, selective surface radioiodination using lactoperoxidase (LPO)-latex beads and immunoprecipitation analysis were performed. We found that cultured EC, similarly to human skin fibroblasts (HSF), expose alpha v beta 3 on both their apical (free) and basal (substratum-attached) surfaces. This held also for other integrins such as alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 1. Immunoprecipitation data were verified by morphological techniques. Immunofluorescence and immunogold-staining of EC with alpha v beta 3, as well as with beta 1 subfamily antibodies, showed a diffuse and granular distribution of these integrins on EC surface. alpha v beta 3 and beta 1 integrins were also detected on the apical membrane of EC at higher magnification by scanning electron microscopy (SEM). Finally, data obtained on cultured EC were confirmed in vivo on immunogold-labeled ultrathin cryosections of human vessels by transmission electron microscopy (TEM). Data indicate, that in addition to their role in promoting EC attachment to extracellular matrix proteins, integrin receptors of EC can be exposed to blood-stream and eventually be available for binding of plasma proteins and circulating cells.