Faecal Incontinence

Fecal incontinence (FI) is an extremely common condition, whose true prevalence is difficult to assess. It was defined as the uncontrolled passage of fecal material recurring for >3 months. Fecal incontinence is related to many etiologic factors, but one of the most frequent causes is secondary to pelvic and/or anal and rectal surgery, childbirth-related damage, or other pelvic trauma. Fecal incontinence after surgery may be elicited by many pelvic, rectal, and anal surgical/obstetric procedures, which contribute through different mechanisms to incontinence. After accurate evaluation, the first line approach with medical and behavioral treatments often fails in treating FI. Rehabilitative therapy and less invasive procedures are preferred before performing standard surgical intervention, while invasive procedures are to be discouraged

Laparoscopic mesogastrium excision for gastric cancer. Only the beginning

Background: Surgery, with the aid of chemotherapy and radiotherapy, is the only curative chance for gastric cancer. Unfortunately, gastric cancer had an elevated recurrence rate, primarily locally. Mesogastrium excision (MGE) during D2 lymphadenectomy has the aim to remove all possible contaminated tissue around the stomach. Methods: PubMed, EMBASE, and the Web of Science (WOS) were systematically searched for MGE reports in gastric cancer up to March 2020. The outcome reported were the number of lymph nodes retrieved, operative time (OT), overall morbidity, intra- and postoperative complications, conversion rate, and length of hospital stay. Results: A total of six studies, including 518 patients, were considered eligible for this analysis. All the studies reported laparoscopic cases. The mean number of lymph nodes retrieved was 36.7 ± 10.1. Mean OT was 240.7 ± 10.1 minutes. One case of conversion is reported. Overall morbidity was 6%. Medium estimated blood loss was 50.2 ± 39.6 mL. Overall length of stay was 10.7 ± 0.7 days. Mean follow-up was 11 ± 1.4 months. Conclusions: Only few studies evaluated this item, and according to the available evidence, MGE is a feasible technique that could be performed, also laparoscopically, in all surgical resections for gastric cancer with curative intent. Further studies are essential to establish the clear indication of this invasive procedure

Evidence on postoperative abdominal binding. A systematic review with meta-analysis of randomized controlled trials

Background: Midline laparotomy is an unavoidable approach to many surgical procedures. Many surgeons prescript the use of postoperative abdominal binder during the first mobilization after surgery. The use and the cost effective of this device is still debated by many surgeons. Methods: PubMed, EMBASE and the CENTRAL were systematically searched for randomized controlled trials (RCT) comparing patients who wore abdominal binder ("binder") and patient who did not wear any abdominal binder ("non-binder") up to March 2020. The primary outcomes measured in the comparison were postoperative pain, pulmonary functions, the entity of physical activity, the comfort. A meta-analysis of relevant studies was performed using RevMan 5.3. Results: wearing an abdominal binder after midline laparotomy seems to reduce postoperative pain on first and third postoperative day, to improve the physical activity on third postoperative day, and not affect pulmonary functions. Generally, an elastic abdominal binder is well tolerated during postoperative. Conclusions: the use of elastic abdominal binder permits a comfortable early postoperative mobilization reducing pain, increases physical activity and seems to not affect pulmonary functions

Minilaparoscopic cholecystectomy versus conventional laparoscopic cholecystectomy. An endless debate

Background: Our systematic review and meta-analysis examine the impact of minilaparoscopic cholecystectomy (MLC) versus conventional laparoscopic cholecystectomy (CLC). Some authors previously compared these surgical approaches without reaching any clear conclusion, since then, further trials have been performed, but an update was needed. Materials and Methods: PubMed, EMBASE, and the CENTRAL were systematically searched for randomized controlled trials comparing MLC versus CLC up to August 2019. The outcome measures used for comparison were operative time (OT), overall morbidity, intra- and postoperative complications, conversion and reintervention rate, length of hospital stay (LOS), postoperative pain (POP), and cosmetic results. A meta-analysis of relevant studies was performed using RevMan 5.3. Results: Fifteen studies, including 863 patients, were considered eligible to collect data and entered the meta-analysis. A total of 415 patients in the MLC group versus 448 in the CLC group were compared. No statistical difference as for overall morbidity, intra- and postoperative complications, conversion and reintervention rate, LOS, and cosmetic results were retrieved among the groups. CLC results faster and MLC shows to be the least painful. Conclusions: According to the available high-level evidence, both surgical approaches resulted substantially equivalent to perform LC, with some advantages of CLC as for OT and of MLC concerning POP. As a consequence, we can conclude that either procedure is superior or inferior to the other one; actually, we are not able to suggest the adoption of any of the two on a routine basis

Functional characterization of the Mycobacterium tuberculosis zinc metallopeptidase Zmp1 and identification of potential substrates

Zinc metallopeptidases of bacterial pathogens are widely distributed virulence factors and represent promising pharmacological targets. In this work, we have characterized Zmp1, a zinc metallopeptidase identified as a virulence factor of Mycobacterium tuberculosis and belonging to the neprilysin (NEP; M13) family, whose X-ray structure has been recently solved. Interestingly, this enzyme shows an optimum activity toward a fluorogenic substrate at moderately acidic pH values (i.e., 6.3), which corresponds to those reported for the Mtb phagosome where this enzyme should exert its pathological activity. Substrate specificity of Zmp1 was investigated by screening a peptide library. Several sequences derived from biologically relevant proteins were identified as possible substrates, including the neuropeptides bradykinin, neurotensin, and neuropeptide FF. Further, subsequences of other small bioactive peptides were found among most frequently cleaved sites, e.g., apelin-13 and substance P. We determined the specific cleavage site within neuropeptides by mass spectrometry, observing that hydrophobic amino acids, mainly phenylalanine and isoleucine, are overrepresented at position P1′. In addition, the enzymatic mechanism of Zmp1 toward these neuropeptides has been characterized, displaying some differences with respect to the synthetic fluorogenic substrate and indicating that the enzyme adapts its enzymatic action to different substrate

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review

Cytidine 5'-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials)

Pelvic Organ Prolapse (POP) Working Group (SICCR): Doubts and Evidence for a Practical Guide

Pelvic Organ Prolapse (POP) can be defined as a downward descent of female pelvic organs, including the bladder, uterus, post-hysterectomy vaginal cuff and the small or large bowel, resulting in protrusion of the vaginal walls, uterus, or both. The International Continence Society includes also rectal prolapses. POP development is multifactorial

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators

Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells

Head and neck cancer (HNC) has frequently an aggressive course for the development of resistance to standard chemotherapy. Thus, the use of innovative therapeutic drugs is being assessed. Bortezomib is a proteasome inhibitor with anticancer effects. In vitro antitumoral activity of Bortezomib was investigated employing human tongue (SCC-15, CAL-27), pharynx (FaDu), salivary gland (A-253) cancer cell lines and a murine cell line (SALTO-5) originated from a salivary gland adenocarcinoma arising in BALB-neuT male mice transgenic for the oncogene neu. Bortezomib inhibited cell proliferation, triggered apoptosis, modulated the expression and activation of pro-survival signaling transduction pathways proteins activated by ErbB receptors and inhibited proteasome activity in vitro. Intraperitoneal administration of Bortezomib delayed tumor growth of SALTO-5 cells transplanted in BALB-neuT mice, protracted mice survival and adjusted tumor microenvironment by increasing tumor-infiltrating immune cells (CD4+ and CD8+ T cells, B lymphocytes, macrophages, and Natural Killer cells) and by decreasing vessels density. In addition, Bortezomib modified the expression of proteasome structural subunits in transplanted SALTO-5 cells. Our findings further support the use of Bortezomib for the treatment of HNC and reveal its ineffectiveness in counteracting the activation of deregulated specific signaling pathways in HNC cell lines when resistance to proteasome inhibition is developed

Insights into immune responses in oral cancer through proteomic analysis of saliva and salivary extracellular vesicles

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOThe development and progression of oral cavity squamous cell carcinoma (OSCC) involves complex cellular mechanisms that contribute to the low five-year survival rate of approximately 20% among diagnosed patients. However, the biological processes essential to tumor progression are not completely understood. Therefore, detecting alterations in the salivary proteome may assist in elucidating the cellular mechanisms modulated in OSCC and improve the clinical prognosis of the disease. The proteome of whole saliva and salivary extracellular vesicles (EVs) from patients with OSCC and healthy individuals were analyzed by LC-MS/MS and label-free protein quantification. Proteome data analysis was performed using statistical, machine learning and feature selection methods with additional functional annotation. Biological processes related to immune responses, peptidase inhibitor activity, iron coordination and protease binding were overrepresented in the group of differentially expressed proteins. Proteins related to the inflammatory system, transport of metals and cellular growth and proliferation were identified in the proteome of salivary EVs. The proteomics data were robust and could classify OSCC with 90% accuracy. The saliva proteome analysis revealed that immune processes are related to the presence of OSCC and indicate that proteomics data can contribute to determining OSCC prognosis.The development and progression of oral cavity squamous cell carcinoma (OSCC) involves complex cellular mechanisms that contribute to the low five-year survival rate of approximately 20% among diagnosed patients. However, the biological processes essential to tumor progression are not completely understood. Therefore, detecting alterations in the salivary proteome may assist in elucidating the cellular mechanisms modulated in OSCC and improve the clinical prognosis of the disease. The proteome of whole saliva and salivary extracellular vesicles (EVs) from patients with OSCC and healthy individuals were analyzed by LC-MS/MS and label-free protein quantification. Proteome data analysis was performed using statistical, machine learning and feature selection methods with additional functional annotation. Biological processes related to immune responses, peptidase inhibitor activity, iron coordination and protease binding were overrepresented in the group of differentially expressed proteins. Proteins related to the inflammatory system, transport of metals and cellular growth and proliferation were identified in the proteome of salivary EVs. The proteomics data were robust and could classify OSCC with 90% accuracy. The saliva proteome analysis revealed that immune processes are related to the presence of OSCC and indicate that proteomics data can contribute to determining OSCC prognosis5FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2009/54067-3; 2010/19278-0470549/2011-4; 301702/2011-0; 470268/2013-1