Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and ...cerebrospinal fluid of MS patients. Interferon β (IFNβ) has been used as a first-line therapy in MS for almost three decades and vitamin D deficiency is a recognized environmental risk factor for MS. Both IFNβ and vitamin D modulate DC functions. Here, we studied the response to 1,25-dihydoxyvitamin D3 (1,25(OH)2D3) of DC obtained with IFNβ/GM-CSF (IFN-DC) compared to classically derived IL4-DC, in three donor groups: MS patients free of therapy, MS patients undergoing IFNβ therapy, and healthy donors. Except for a decreased CCL2 secretion by IL4-DC from the MS group, no major defects were observed in the 1,25(OH)2D3 response of either IFN-DC or IL4-DC from MS donors compared to healthy donors. However, the two cell models strongly differed for vitamin D receptor level of expression as well as for basal and 1,25(OH)2D3-induced cytokine/chemokine secretion. 1,25(OH)2D3 up-modulated IL6, its soluble receptor sIL6R, and CCL5 in IL4-DC, and down-modulated IL10 in IFN-DC. IFN-DC, but not IL4-DC, constitutively secreted high levels of IL8 and of matrix-metalloproteinase-9, both down-modulated by 1,25(OH)2D3. DC may contribute to MS pathogenesis, but also provide an avenue for therapeutic intervention. 1,25(OH)2D3-induced tolerogenic DC are in clinical trial for MS. We show that the protocol of in vitro DC differentiation qualitatively and quantitatively affects secretion of cytokines and chemokines deeply involved in MS pathogenesis.
In this study, a new methodology for designing and creating a custom-made template for maxillofacial surgery has been developed. The custom-made template can be used both for cutting and ...repositioning of the mandible arches for executing a BSSO (bilateral sagittal split osteotomy) treatment. The idea was developed in order to give the possibility of using a custom-made template with standard plates, thus reducing long times, high costs and low availability of custom-made plates; this represents the proof of novelty of the proposed template, based on a well-established methodology. The methodology was completely developed in the CAD virtual environment and, after the surgeons’ assessment, an in-vitro experiment by a maxillofacial surgeon was performed in order to check the usability and the versatility of the system, thanks to the use of additive manufacturing technologies. When computer-aided technologies are used for orthognathic surgery, there are significant time and cost savings that can be realised, as well as improved performance. The cost of the whole operation is lower than the standard one, thanks to the use of standard plates. To carry out the procedures, the proposed methodology allows for inexpensive physical mock-ups that enable the BSSO procedure to be performed.
Introduction
Bowel dysfunction (BD) is reported as a common and disabling symptom in multiple sclerosis (MS) patients. To date, no studies have explored the prevalence of these symptoms in a large ...multicenter outpatient setting. The aims of the present study are to assess: (i) the prevalence of BD in a large multicenter Italian MS population, and (ii) the correlation between clinico-demographic variables and the severity of BD.
Methods
Each of the nine participating center screened MS patients prospectively: 1100 subjects were enrolled. All patients underwent the Expanded Disability Status Scale (EDSS) and completed the Neurogenic Bowel Dysfunction score (NBDs). Multivariable linear and logistic regression models were used to assess the association between NBDs and several clinico-demographic variables.
Results
Fourteen percent of MS patients showed a moderate/severe BD (NBDs > 10); this percentage increased in patients with high disability, ranging from 26 to 32%. Moderate/severe BD was more frequent in MS patients with: progressive phenotypes, higher disability, older age, and longer disease duration. NBDs severity was predicted by female sex, ambulation impairment and bladder symptoms.
Conclusion
This study confirms the relatively high prevalence of moderate/severe BD in a large, multicenter, unselected, outpatient MS population. BD appears to be mainly associated to female sex and MS-related disability.
Pregnancy-related issues in women with multiple sclerosis (MS) have been receiving increasing attention, with particular interest for the use of disease-modifying therapies (DMTs) before conception, ...during pregnancy, and postpartum, including breastfeeding. The risk of relapse is higher in the early postpartum period, especially in cases of significant disease activity prior to pregnancy, and thus treatment resumption and/or switching strategies might be necessary. Moreover, breastfeeding provides unmatched health benefits for babies and mothers, and is recommended as the best source of nutrition for infants. Furthermore, a protective role of breastfeeding on MS disease course has not been fully demonstrated and it remains debatable. At the same time, a source of concern is the potential transfer of DMTs into breastmilk and the resulting infant exposure. The use of most DMTs is unlicensed during breastfeeding mainly due to the limited data available on the excretion in human milk and on the effects on infants' exposure. Consequently, women have to face the difficult challenge of choosing between breastfeeding and DMT resumption. The present narrative review summarizes and discusses the available evidence on the safety of DMTs during breastfeeding and the relative approved labels. At the time of diagnosis of MS, specific counseling should be offered to women of childbearing age, making them aware of the possible therapeutic options and their impact on pregnancy and breastfeeding. Women can be encouraged to breastfeed, if clinically feasible, following a review of their medications and clinical status, with a personalized approach.
Nabiximols (THC/CBD Oromucosal Spray, Sativex) is used as an add-on therapy to treat moderate to severe spasticity of Multiple Sclerosis (MS).
To examine the impact of physiotherapy (PT) programs on ...effectiveness and persistence of nabiximols treatment in people with MS-related spasticity.
This is an observational multicenter study with a follow-up period of 12 weeks, conducted in routine care settings in Italy. Patients with moderate to severe MS-related spasticity who started nabiximols were included. Spasticity was evaluated by the patient-rated 0-10 numerical rating scale (NRS). Clinical data were collected at baseline (T0), 4 weeks (T1) and 12 weeks (T2) months after enrollment.
A total of 297 MS patients were selected, 290 completed the 3 months follow-up period. Mean NRS scores were 7.6 ± 1.1 at T0, 5.8 ± 1.4 at T1 and 5.5 ± 1.5 at T2. At T1, 77% of patients reached ≥20% improvement (initial response, IR); 22% reached ≥30% improvement (clinically relevant response, CRR). At T1, patients undergoing PT had a higher probability to reach CRR (Odds Ratio = 2.6 95% CI 1.3-5.6, p = 0.01). Nabiximols was discontinued in 30/290 (10.3%) patients at T1 (early discontinuers) and in 71/290 (24.5%) patients at T2 (late discontinuers). The probability of being late discontinuers was reduced in patients undergoing PT (Hazard Ratio = 0.41; 95% CI 0.23-0.69, p = 0.001).
Our real-life study confirms nabiximols' effectiveness in MS-related spasticity and suggests that the association of a PT program may improve overall response and persistence to nabiximols treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Orthognathic surgery allows broad-spectrum deformity correction involving both aesthetic and functional aspects on the TMJ (temporo-mandibular joint) and on the facial skull district. The combination ...of Reverse Engineering (RE), Virtual Surgery Planning (VSP), Computer Aided Design (CAD), Additive Manufacturing (AM), and 3D visualization allows surgeons to plan, virtually, manipulations and the translation of the human parts in the operating room. This work’s aim was to define a methodology, in the form of a workflow, for surgery planning and for designing and manufacturing templates for orthognathic surgery. Along the workflow, the error chain was checked and the maximum error in virtual planning was evaluated. The three-dimensional reconstruction of the mandibular shape and bone fragment movements after segmentation allow complete planning of the surgery and, following the proposed method, the introduction of both the innovative evaluation of the transversal intercondylar distance variation after mandibular arch advancement/set and the possibility of use of standard plates to plan and realize a customized surgery. The procedure was adopted in one clinical case on a patient affected by a class III malocclusion with an associated open bite and right deviation of the mandible with expected good results. Compared with the methods from most recent literature, the presented method introduces two elements of novelty and improves surgery results by optimizing costs and operating time. A new era of collaboration among surgeons and engineer has begun and is now bringing several benefits in personalized surgery.
Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational ...study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities.
We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (
=30; 23F/7M, 40 ± 8.14 years) or a relapse (
=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (
=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis.
Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3.
Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis.
ClinicalTrials.gov, identifier NCT04380220.
Virtual surgical planning for CAD/CAM mandibular reconstruction by titanium prosthesis was recently reported for resected cases. Even if some advantages are evident, difficulties that may arise for ...TMJ function after reconstruction originate from prosthesis contamination through oral mucosa dehiscence. In these two cases reported of mandibular reconstruction after resection of ameloblastoma by custom-made CAD/CAM titanium prosthesis, the procedures were aimed to preserve the TMJ glenoid cavity and articular disc avoiding functional problems for hemi-mandibular resections that included the condyle (as in case #1) or with condylar preservation (as in case #2) and avoiding intraoral incisions in both cases. The entire surgical planning and prosthetic fabrication were explained with specifications and the sequence of the surgical procedure. Finite elements analysis (FEA) was performed to check the force distribution and efficacy of the prosthetic device (case 1 with hemi-mandibular resection and rehabilitation). Although successful in these two cases, surgical reconstruction of the mandibular defect after resection by a CAD-CAM custom-made prosthesis still shows some drawbacks and failure risks. Several advantages of this technique and the surgical success in these two cases were presented, but limitations and side effects must be considered when cases are selected.
Condylar neck and sub-condylar fractures of the mandible are a frequent occurrence in maxillofacial surgery. The indication for surgical treatment of these fractures has changed over time, and ...several techniques have been developed with different results in the attempt to avoid the most worrisome adverse event, i.e., facial nerve injury. In this study, we present a new technique that combines an intraoral and a cutaneous pre-auricular access, which allows for easy and safe access to the surgical site, preventing facial nerve injury and avoiding surgical scars in high-impact aesthetic areas of the neck. Five consecutive patients affected by condylar neck or sub-condylar fractures were treated at a single institution using a combined intraoral and pre-auricular access. Results were evaluated after three months from surgery in terms of mandibular mobility, occurrence of complications, and patient's satisfaction. All five patients had good outcome, with complete healing of the fracture and no occurrence of complications, including no facial nerve palsy. A key point of the technique is the safe reduction of the two mandibular fragments realized by a combined intraoral and a cutaneous pre-auricular surgical access. The periosteal plan of the ramus can be widely and safely elevated with the intraoral approach and connected to the condylar bone plane by the pre-auricular cutaneous approach without any need for soft tissue dissection at the fracture rim, thereby avoiding facial nerve injuries. Wide ramus periosteum elevation creates an "optical space", allowing fragment reduction and fixation under direct oblique view without any endoscopic need. Our results strongly suggest that with our technique it is possible to treat sub-condylar and condylar neck fractures safely, avoiding facial nerve injury, which is an unacceptable complication due to its heavy impact on a patient's life.
Disease recurrence and progression of ovarian cancer is common with the development of platinum-resistant or refractory disease. This is due in large part to the presence of chemo-resistant cancer ...stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. We developed a CSCs drug cytotoxicity assay (ChemoID) to identify the most effective chemotherapy treatment from a panel of FDA approved chemotherapies.
Ascites and pleural fluid samples were collected under physician order from 45 consecutive patients affected by 3rd-5th relapsed ovarian cancer. Test results from the assay were used to treat patients with the highest cell kill drugs, taking into consideration their health status and using dose reductions, as needed. A retrospective chart review of CT and PET scans was used to determine patients' outcomes for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS).
We observed that recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in the median PFS corresponding to 5.4 months (3rd relapse), 3.6 months (4th relapse), and 3.9 months (5th relapse) when compared to historical data. Additionally, we observed that ovarian cancer patients identified as non-responders by the CSC drug response assay had 30 times the hazard of death compared to those women that were identified as responders with respective median survivals of 6 months vs. 13 months. We also found that ChemoID treated patients on average had an incremental cost-effectiveness ratio (ICER) between -$18,421 and $7,241 per life-year saved (LYS).
This study demonstrated improved PFS and OS for recurrent ovarian cancer patients treated with assay-guided chemotherapies while decreasing the cost of treatment.
•Ovarian cancer progression and recurrence is mostly attributed to the presence of cancer stem cells (CSCs), which are chemo-resistant.•Eliminating CSCs is a strategy that could improve patients' outcome.•We developed a CSC drug cytotoxicity assay to identify the most effective chemotherapy treatment from a panel of FDA approved chemotherapies.•Recurrent ovarian cancer patients treated with high-cell kill chemotherapy agents guided by the CSCs drug response assay had an improvement in the median PFS when compared to historical data.