Preclinical discovery and development of fingolimod for the treatment of multiple sclerosis

ABSTRACTIntroduction: Fingolimod, the first oral disease-modifying treatment (DMT) in multiple sclerosis (MS), is a sphingosine 1-phosphate receptor (S1PR) ligand. Approved in 2010, fingolimod has ..

A six sigma DMAIC methodology as a support tool for health technology assessment of two antibiotics

Health Technology Assessment (HTA) and Six Sigma (SS) have largely proved their reliability in the healthcare context. The former focuses on the assessment of health technologies to be introduced in a healthcare system. The latter deals with the improvement of the quality of services, reducing errors and variability in the healthcare processes. Both the approaches demand a detailed analysis, evidence-based decisions, and efficient control plans. In this paper, the SS is applied as a support tool for HTA of two antibiotics with the final aim of assessing their clinical and organizational impact in terms of postoperative Length Of Stay (LOS) for patients undergoing tongue cancer surgery. More specifically, the SS has been implemented through its main tool, namely the DMAIC (Define, Measure, Analyse, Improve, Control) cycle. Moreover, within the DMAIC cycle, a modelling approach based on a multiple linear regression analysis technique is introduced, in the Control phase, to add complementary information and confirm the results obtained by the statistical analysis performed within the other phases of the SS DMAIC. The obtained results show that the proposed methodology is effective to determine the clinical and organizational impact of each of the examined antibiotics, when LOS is taken as a measure of performance, and guide the decision-making process. Furthermore, our study provides a systematic procedure which, properly combining different and well-assessed tools available in the literature, demonstrated to be a useful guidance for choosing the right treatment based on the available data in the specific circumstance

Three-dimensional superimposition for patients with facial palsy: an innovative method for assessing the success of facial reanimation procedures

Facial palsy is a severe condition that may be ameliorated by facial reanimation, but there is no consensus about how to judge its success. In this study we aimed to test a new method for assessing facial movements based on 3-dimensional analysis of the facial surfaces. Eleven patients aged between 42 and 77 years who had recently been affected by facial palsy (onset between 6 and 18 months) were treated by an operation based on triple innervation: the masseteric to temporofacial nerve branch, 30% of the hypoglossal fibres to the cervicofacial nerve branch, and the contralateral facial nerve through two cross-face sural nerve grafts. Each patient had five stereophotogrammetric scans: at rest, smiling on the healthy side (facial stimulus), biting (masseteric stimulus), moving the tongue (hypoglossal stimulus), and corner-of-the-mouth smile (Mona Lisa). Each scan was superimposed onto the facial model of the "rest" position, and the point-to-point root mean square (RMS) value was automatically calculated on both the paralysed and the healthy side, together with an index of asymmetry. One-way and two-way ANOVA tests, respectively, were applied to verify the significance of possible differences in the RMS and asymmetry index according to the type of stimulus (p = 0.0329) and side (p < 0.0001). RMS differed significantly according to side between the facial stimulus and the masseteric one on the paralysed side (p = 0.0316). Facial stimulus evoked the most asymmetrical movement, whereas the masseteric produced the most symmetrical expression. The method can be used for assessing facial movements after facial reanimation

A health technology assessment between two pharmacological therapies through Six Sigma: the case study of bone cancer

Purpose: Head and neck cancers are multi-factorial diseases that can affect many sides of people's life and are due to a lot of risk factors. According to their characteristics, the treatment can be surgical, use of radiation or chemotherapy. The use of a surgical treatment can lead to surgical infections that are a main theme in medicine. At the University hospital of Naples “Federico II”, two antibiotics were employed to tackle the issue of the infections and they are compared in this paper to find which one implies the lowest length of hospital stay (LOS) and the reduction of infections. Design/methodology/approach: The Six Sigma methodology and its problem-solving strategy DMAIC (define, measure, analyse, improve, control), already employed in the healthcare sector, were used as a tool of a health technology assessment between two drugs. In this paper the DMAIC roadmap is used to compare the Ceftriaxone (administered to a group of 48 patients) and the association of Cefazolin plus Clindamycin (administered to a group of 45 patients). Findings: The results show that the LOS of patients treated with Ceftriaxone is lower than those who were treated with the association of Cefazolin plus Clindamycin, the difference is about 41%. Moreover, a lower number of complications and infections was found in patients who received Ceftriaxone. Finally, a greater number of antibiotic shifts was needed by patients treated with Cefazolin plus Clindamycin. Research limitations/implications: While the paper enhances clearly the advantages for patients' outcomes regarding the LOS and the number of complications, it did not analyse the costs of the two antibiotics. Practical implications: Employing the Ceftriaxone would allow the Department of Maxillofacial Surgery to obtain lower LOS and a limited number of complications/infections for recovered patients, consequently reducing the hospitalization costs. Originality/value: There is a double value in this paper: first of all, the comparison between the two antibiotics gives an answer to one of the main issues in medicine that is the reduction of hospital-acquired infections; secondly, the Six Sigma through its DMAIC cycle can be employed also to compare two biomedical technologies as a tool of health technology assessment studies

A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice

The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-γ. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-γ fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-γ, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism

The role of bacterial colonization of the suture thread in early identification and targeted antibiotic treatment of surgical site infections: A prospective cohort study

Background: The aim of the present study is to investigate the role of the colonization of suture thread to identify patients at risk of developing a surgical site infection (SSI) after clean surgical procedures. Methods: Patients who underwent elective clean surgery procedures at the Surgery Unit of the AOU-University of Campania Luigi Vanvitelli in a 21-month period were prospectively enrolled. For each patient, a synthetic absorbable thread in Lactomer 9-1 was inserted into the surgical site at the end of surgery and microbiologically evaluated after 48 h. Antibiotic prophylaxis was chosen according to international guidelines. Results: A total of 238 patients were enrolled; 208 (87.4%) of them were subjected to clean procedures without the placement of prosthesis, and 30 (12.6%) with prosthesis. Of the 238 patients, 117 (49.2%) underwent an antimicrobial prophylaxis. Overall, 79 (33.2%) patients showed a bacterial colonization of the thread: among the 208 without the implantation of prosthesis, 19 (21.8%) of the 87 with antibiotic prophylaxis and in 58 (47.9%) of the 121 without it; among the 30 patients with the implantation of prosthesis, only two patients showed a colonized thread. The patients with antibiotic prophylaxis developed a colonization of the thread less frequently than those without it (17.9% vs. 47.9%, p &lt; 0.001). SSI was observed in six (2.5%) patients, all of them showing a colonized thread (7.6% vs. 0%, p &lt; 0.001). The bacteria identified in colonized threads were the same as those found in SSIs. Conclusions: Our study presents a new method that is able to precociously assess patients who have undergone clean procedures who may develop SSI, and identify the microorganism involved

Effect of Probiotic Administration on Serum Tryptophan Metabolites in Pediatric Type 1 Diabetes Patients

Type 1 diabetes (T1D) is characterized by anomalous functioning of the immuno regulatory, tryptophan-catabolic enzyme indoleamine 2,3 dioxygenase 1 (IDO1). In T1D, the levels of kynurenine—the first byproduct of tryptophan degradation via IDO1—are significantly lower than in nondiabetic controls, such that defective immune regulation by IDO1 has been recognized as potentially contributing to autoimmunity in T1D. Because tryptophan catabolism—and the production of immune regulatory catabolites—also occurs via the gut microbiota, we measured serum levels of tryptophan, and metabolites thereof, in pediatric, diabetic patients after a 3-month oral course of Lactobacillus rhamnosus GG. Daily administration of the probiotic significantly affected circulating levels of tryptophan as well as the qualitative pattern of metabolite formation in the diabetic patients, while it decreased inflammatory cytokine production by the patients. This study suggests for the first time that a probiotic treatment may affect systemic tryptophan metabolism and restrain proinflammatory profile in pediatric T1D

Identification of a 2-propanol analogue modulating the non-enzymatic function of indoleamine 2,3-dioxygenase 1

Abstract Indoleamine 2,3 dioxygenase 1 (IDO1) is a metabolic enzyme that catalyzes the conversion of the essential amino acid tryptophan (Trp) into a series of immunoactive catabolites, collectively known as kynurenines. Through the depletion of Trp and the generation of kynurenines, IDO1 represents a key regulator of the immune responses involved in physiologic homeostasis as well as in neoplastic and autoimmune pathologies. The IDO1 enzyme has been described as an important immune checkpoint to be targeted by catalytic inhibitors in the treatment of cancer. In contrast, a defective expression/activity of the enzyme has been demonstrated in autoimmune diseases. Beside its catalytic activity, the IDO1 protein is endowed with an additional function associated with the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which, once phosphorylated, bind SHP phosphatases and mediate a long-term immunoregulatory activity of IDO1. Herein, we report the screening of a focused library of molecules bearing a propanol core by a protocol combining microscale thermophoresis (MST) analysis and a cellular assay. As a result, the combined screening identified a 2-propanolol analogue, VIS351, as the first potent activator of the ITIM-mediated function of the IDO1 enzyme. VIS351 displayed a good dissociation constant (Kd = 1.90 μM) for IDO1 and a moderate cellular inhibitor activity (IC50 = 11.463 μM), although it did not show any catalytic inhibition of the recombinant IDO1 enzyme. Because we previously demonstrated that the enzymatic and non-enzymatic (i.e., ITIM-mediated) functions of IDO1 reside in different conformations of the protein, we hypothesized that in the cellular system VIS351 may shift the dynamic conformational balance towards the ITIM-favoring folding of IDO1, resulting in the activation of the signaling rather than catalytic activity of IDO1. We demonstrated that VIS351 activated the ITIM-mediated signaling of IDO1 also in mouse plasmacytoid dendritic cells, conferring those cells an immunosuppressive phenotype detectable in vivo. Thus the manuscript describes for the first time a small molecule as a positive modulator of IDO1 signaling function, paving the basis for an innovative approach to develop first-in-class drugs acting on the IDO1 target