Fluphenazine-Induced Neurotoxicity with Acute Almost Transient Parkinsonism and Permanent Memory Loss: Lessons from a Case Report.

We report the singular case of a 31-year-old woman who developed very serious Fluphenazine-induced parkinsonism over a few days due to a doubly incongruent drug prescription by indication and dosage having been applied to a healthy subject over one week instead of seven months. Unlike gradual drug-induced parkinsonism, our patient experienced acute extrapyramidal syndrome (EPS), reaching significant motor and sphincter disability in just a few days, followed by a gradual incomplete recovery over more than six months. In fact, after drug discontinuation, hypomimia and slight left hemi-somatic rigidity with bradykinesia remained, as well as stable non-progressive memory disturbances. Despite bio-humoral and instrumental investigations and DaTScan were negative, MRI post-analysis evidenced a 6.5% loss in brain volume. Specifically, irreversible cortical and sub-cortical grey matter reduction and cerebrospinal fluid space enlargement with spared white matter were found. Our observations suggest that the sudden availability of Fluphenazine results in a kind of plateau effect of parkinsonism presentation, partially reversible due to the neurotoxic drug effect on the cortical and sub-cortical grey matter, resulting in asymmetric EPS and stable memory loss, respectively. Our report confirms the debated neurotoxicity of first-generation neuroleptics and the postulated theory of differential susceptibility to the cytotoxic stressors on the central nervous system.

Effectiveness of Capsule Endoscopy and Double-Balloon Enteroscopy in Suspected Complicated Celiac Disease.

BACKGROUND & AIMS: Complicated celiac disease (CCD) is a rare but severe condition with a poor prognosis. Guidelines recommend use of capsule endoscopy (CE) to explore the small bowel (SB), followed by a double-balloon enteroscopy (DBE) in selected cases with suspected CCD. Our study aimed to evaluate the diagnostic yield (DY) of CE and DBE in identifying and monitoring CCD. METHODS: Consecutive suspected CCD patients were enrolled prospectively to undergo CE and/or DBE in the presence of: persistent symptoms despite a correct gluten-free diet (GFD), increased anti-transglutaminase antibodies titer, lack of adherence to the GFD, and CCD monitoring. The DY of CE and DBE were calculated. The incidence of neoplastic complications and mortality were assessed. RESULTS: In total, 130 patients (97 women; age, 49 ± 16 y) underwent 151 CEs and 23 DBEs. The DY of CE was 46%. Patients older than age 50 years (at CE examination or at CD diagnosis) with a CD duration shorter than 5 years were at higher risk of positive CE (relative risk, 1.6 and 1.7 in case of enrollement or CD diagnosis after 50 years of age, and 1.5 in case of short CD duration; P < .05) than their counterparts. Up to 40% of SB lesions were unreachable by upper endoscopy. At the end of the diagnostic work-up, 25 patients with premalignant/malignant lesions were identified: 12 type 1 refractory CD (RCD-1), 7 type 2 RCD (RCD-2), and 6 enteropathy-associated T-cell lymphoma (EATL). Six patients died: 2 patients with RCD-2 and 4 patients with EATL. CONCLUSIONS: In case of suspected CCD, CE should be the first-line approach to detect complications and to identify patients deserving DBE. Older and symptomatic patients with suspected CCD deserve a careful evaluation of the SB, especially during the first years after diagnosis.

GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review.

Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.

Changes in Brain Volumes Are Relevant during Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: Lessons from a Case Report.

This is a case report concerning a Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) with cerebellar localization and wakefulness disturbances. Awakening and clinical improvement dramatically occurred as soon as the immune reconstitution inflammatory syndrome (IRIS) took place, being it mild in nature and colocalizing with the PML lesion. In these ideal experimental conditions, we applied brain magnetic resonance imaging post-analysis in order to know changes in brain volumes underlying the pathological process over the infection period. White matter volume increased with a decrease in grey matter during IRIS. Conversely, we found a constant increase in cerebrospinal fluid volume throughout the duration of PML, suggesting a widespread abiotrophic effect, far from the lesion. Furthermore, brain parenchymal fraction significantly decreased as expected while the total brain volume remained stable at all times. Neurodegeneration is the main contributor to the steady disability in Natalizumab-associated PML. This process is thought to be widespread and inflammatory in nature as well as sustained by IRIS and humoral factors derived from the PML lesion.

Safety of occasional ingestion of gluten in patients with celiac disease: a real-life study.

BACKGROUND: Gluten-free diet (GFD) decreases the quality of life of celiac disease (CD) patients, who frequently ask to occasionally ingest gluten-containing food. We evaluated CD patients reporting voluntary and occasional transgressions to their GFD. METHODS: From October 2017 to September 2018, the patients reporting occasional and voluntary gluten ingestion (GFD-noncompliant) were prospectively enrolled. These patients underwent clinical examination, blood tests, duodenal biopsy, capsule enteroscopy (CE), and a validated food-frequency questionnaire (FFQ) assessing the frequency and quantity of gluten intake. Mortality was calculated and compared to the general population. A group of patients on strict GFD (GFD-adherent) acted as controls. RESULTS: One thousand three hundred seventy-eight CD patients were evaluated during the study period. One hundred nine (8%) reported occasional (weekly or monthly) voluntary ingestion of gluten. The mean gluten intake was 185.2 ± 336.9 g/year, and the duration of their incorrect GFD was 8.6 ± 6.9 years. Among the noncompliant patients, 57% did not present any histological alteration; furthermore, the Marsh score profile was not different between compliant and noncompliant patients. Seventy percent did not present any alteration at CE. Seventy-five percent of patients reported no gastrointestinal symptoms after gluten ingestion. Twenty-three percent of patients in the GFD-noncompliant group presented positive tTG-IgA. No association was found between gluten intake, clinical symptoms, and biomarkers. Mortality was not different between the groups and the general population. CONCLUSIONS: Our results are that in a real-life scenario, a group of CD patients on long-term gluten intake showed no significant clinical symptoms or small bowel damage, thus suggesting that a degree of tolerance towards gluten consumption can be reached.

Efficacy and safety of device-assisted enteroscopy ERCP in liver transplantation: A systematic review and meta-analysis.

BACKGROUND: Enterobiliary anastomoses are the main source of complications after liver transplantation. An endoscopic approach combining device-assisted enteroscopy and ERCP (DAE-ERCP) is technically feasible in postsurgical anatomy. AIMS: This study aimed at assessing the efficacy, feasibility, and safety of DAE-ERCP in liver-transplanted patients (LT) and other subsets (non-LT). METHODS: A systematic review and meta-analysis of studies involving DAE procedures in LT patients (between January 2000 and May 2017) was conducted. The main endpoints were as follows: endoscopic, diagnostic, therapeutic, and overall success rates, complications, and the need for surgery. RESULTS: A total of 155 studies were retrieved, and 6 relevant trials were analyzed. Overall, 132 subjects (72 LT and 60 non-LT) undergoing 257 DAE-ERCP (135 and 122) were included. Complications were rare (4/257), and no deaths occurred. These are the pooled success rates among LT and non-LT patients: 80%-100% and 82%-95% (enteroscopic), 75%-100% and 89%-100% (diagnostic), 67%-100% and 92%-100% (therapeutic), and 60%-100% and 79%-83% (overall results). The requirement for surgery was similar in the two subgroups. CONCLUSION: In managing biliary complications, the high diagnostic and therapeutic success rates of DAE-ERCP combined with its safety and feasibility encourage its application as a first-line approach to transplanted patients.

Small-bowel capsule endoscopy in patients with celiac disease, axial versus lateral/panoramic view: Results from a prospective randomized trial.

BACKGROUND AND AIM: Capsule enteroscopy (CE) is recommended in the management of complicated celiac disease (CD). However, published data are derived from axial-view capsule systems. No data are available on the use of lateral/panoramic view capsules. This study aimed at evaluating the diagnostic yield and efficacy of the lateral/panoramic versus the axial view capsule system in CD. METHODS: Consecutive CD patients were enrolled in a prospective monocentric study. Each patient ingested an axial (PillCam SB3) and a lateral/panoramic (CapsoCam Plus) view capsule with a 3-h interval in a randomized order. Two experts blindly evaluated the CE carried out. A third expert reviewed the videos in cases of discordance. RESULTS: Twenty-five CD patients were enrolled (four males, age at CE 51.2 ± 16.6 years, age at CD diagnosis 41.7 ± 20.6, years on a gluten-free diet [GFD] 9.6 ± 9.4). Indications at CE were refractory CD in nine cases, non-responsiveness to GFD in 10 and GFD non-compliance in six. A positive finding was evidenced in 15 (60%) and 13 (52%) cases by CapsoCam and PillCam respectively (not significant). Atrophy was detected by both capsules. Considering the percentage of the small-bowel mucosa presenting atrophy signs, mean values were 22% ± 35 and 20% ± 29 for lateral/panoramic and axial systems, respectively (not significant). Compared to duodenal histology, PillCam correctly identified 80% of patients with SB atrophy, whereas CapsoCam identified 73% of cases. CONCLUSIONS: Lateral/panoramic view CE is effective in the detection of small-bowel atrophy in CD and presents good sensitivity and specificity when compared to histology.

Endoscopic ultrasonography and small-bowel endoscopy: Present and future.

Over the last decade, impressive technological advances have occurred in ultrasonography and small-bowel endoscopy. Nowadays, endoscopic ultrasonography is an essential diagnostic tool and a therapeutic weapon for pancreatobiliary disorders. Capsule endoscopy and device-assisted enteroscopy have quickly become the reference standard for the diagnosis of small-bowel luminal diseases, thereby leading to radical changes in diagnostic and therapeutic pathways. We herein provide an up-to-date overview of the latest advances in endoscopic ultrasonography and small-bowel endoscopy, focusing on the emerging paradigms and technological innovations that might improve clinical practice in the near future.

Metastases of Hepatocellular Carcinoma Misdiagnosed as Isolated Hypertrophic Cardiomyopathy.

At present, cardiac metastasis of hepatocellular carcinoma is rarely mentioned in the literature. We report a hepatocellular carcinoma patient with cardiac metastasis misdiagnosed as hypertrophic cardiomyopathy in 2011. Two years later, on presentation of syncope, an abnormal ventricular septal size was recorded by ultrasound scan, and was subsequently shown by magnetic resonance imaging to be a tumour lesion. A myocardial biopsy confirmed infiltration of hepatocellular carcinoma. This observation underlines the risk of hepatocellular carcinoma cardiac metastasis, manifested in its infiltrative form as hypertrophic cardiomyopathy. In conclusion, we suggest that the ultrasound appearance of hypertrophic cardiomyopathy in hepatocellular carcinoma patients should be seen as a "red flag" and recommend the introduction of magnetic resonance imaging assessment of transplant candidates.

Dramatic recovery of steroid-refractory relapsed multiple sclerosis following Fingolimod discontinuation using selective immune adsorption.

BACKGROUND: Selective immune adsorption (SIA) is an emerging method for treating immune-mediated neurological diseases, given its superior safety profile compared to plasma exchange (PEX). However, the available literature concerning Multiple Sclerosis includes no cases of SIA applied to steroid-refractory rebound after Fingolimod discontinuation. CASE PRESENTATION: Here we report the case of a 32-year-old woman suffering from multiple sclerosis treated with Fingolimod and admitted to a Multiple Sclerosis Centre after drug discontinuation due to the occurrence of lymphopenia. During the few weeks preceding admission, the patient experienced progressive and severe neurological deterioration that did not respond to an initial cycle of pulsed high doses of intravenous 6-methyl prednisolone (IVMP). Given the ineffectiveness of a second cycle of IVMP, the patient was treated with plasma immunoadsorption, leading to dramatic functional recovery. The patient then started a neuro-rehabilitation program. About one month after the final SIA procedure the patient started Natalizumab-based therapy, while maintaining a stable neurological condition. We noted significant modification of C3/C4 complement components and total gamma globulin concentrations (IgG) during SIA. CONCLUSIONS: Our observations show that however serious, steroid-refractory neurological deterioration occurring after Fingolimod discontinuation in multiple sclerosis can be treated with selective immune-adsorption therapy which thus represents a good alternative in these cases. It could be speculated that this clinical condition was associated with pattern II of demyelination, given the good response to a form of treatment that acts on autoantibodies. Thus, SIA represented an effective therapeutic strategy for this case of relapsed MS as steroid-resistent rebound post Fingolimod cessation.

Multi-Criterial Model for Weighting Biological Risk Factors in Multiple Sclerosis: Clinical and Health Insurance Implications.

The etiology of Multiple Sclerosis (MS) remains undetermined. Its pathogenic risk factors are thought to play a negligible role individually in the development of the disease, instead assuming a pathogenic role when they interact with each other. Unfortunately, the statistical weighting of this pathogenic role in predicting MS risk is currently elusive, preventing clinical and health insurance applications. Here, we aim to develop a population-based multi-criterial model for weighting biological risk factors in MS; also, to calculate the individual MS risk value useful for health insurance application. Accordingly, among 596 MS patients retrospectively assessed at the time of diagnosis, the value of vitamin D < 10 nm/L, BMI (Body Mass Index) < 15 Kg/m2 and >30 Kg/m2, female sex, degree of family kinship, and the range of age at onset of 20-45 years were considered as biological risk factors for MS. As a result, in a 30-year-old representative patient having a BMI of 15 and second degree of family kinship for MS, the major developmental contributor for disease is the low vitamin D serum level of 10 nm/L, resulting in an MS risk of 0.110 and 0.106 for female and male, respectively. Furthermore, the Choquet integral applied to uncertain variables, such as biological risk factors, evidenced the family kinship as the main contributor, especially if coincident with the others, to the MS risk. This model allows, for the first time, for the risk stratification of getting sick and the application of the health insurance in people at risk for MS.

Dementia-Associated Compulsive Singing (DACS): Presentation of Unpublished Clinical Cases Miniseries.

Dementia-associated compulsive singing (DACS) is a neurotransmettitorial-based behavioral disturbance, characterized by an unabating melodic expression, occurring in patients that suffer from evolved dementia. Previously described only as a "punding" aspect of the dopamine dysregulation syndrome (DDS) in the Parkinson's disease (PD), compulsive singing has now been described, for the first time, in four non-PD patients effectively treated with Haloperidol or Quetiapine. Unlike the DDS-associated conditions, in our cases DACS is not pharmacologically induced, being that all patients were L-dopa-free. We detected a diffuse hyperintensity of the white matter and brain atrophy, with insular shrinkage as well as ventricular system and/or sub-arachnoid space enlargement in our DACS patients. Furthermore, similarly to the other behavioral symptoms of dementia, DACS also seems to be correlated to the degree of cognitive and functional impairment, rather than its subtype. In conclusion, DACS is a non-cognitive, unpublished clinical aspect of evolved dementia, which is interesting due to the involvement of the extra-nigral dopaminergic system, resulting in an unabating altered behavior, but also to the enrichment of our knowledge in the involutional diseases of the central nervous system and their physiopathological manifestations.

Capsule enteroscopy versus small-bowel ultrasonography for the detection and differential diagnosis of intestinal diseases.

BACKGROUND/AIMS: Capsule enteroscopy (CE) and intestinal ultrasonography (IUS) are techniques that are currently used for investigating small-bowel (SB) diseases. The aim of this study was to compare the main imaging findings and the lesion detection rate (LDR) of CE and IUS in different clinical scenarios involving the SB. METHODS: We retrospectively enrolled patients who underwent CE and IUS for obscure gastrointestinal bleeding (OGIB), complicated celiac disease (CeD), and suspected or known inflammatory bowel disease (IBD). We evaluated the LDR of both techniques. The accuracy of IUS was determined using CE as the reference standard. RESULTS: A total of 159 patients (113 female; mean age, 49±19 years) were enrolled. The LDR was 55% and 33% for CE and IUS (p<0.05), respectively. Subgroup analysis showed that the LDR of CE was significantly higher than that of IUS in patients with OGIB (62% vs. 14%, p<0.05) and CeD (55% vs. 35%, p<0.05). IUS showed a similar LDR to CE in patients with suspected or known IBD (51% vs. 46%, p=0.83). CONCLUSION: CE should be preferred in cases of OGIB and CeD, whereas IUS should be considered an early step in the diagnosis and follow-up of IBD even in patients with a proximal SB localization of the disease.

GANAB as a Novel Biomarker in Multiple Sclerosis: Correlation with Neuroinflammation and IFI35.

Multiple sclerosis (MS) still lacks reliable biomarkers of neuroinflammation predictive for disease activity and treatment response. Thus, in a prospective study we assessed 55 MS patients (28 interferon (IFN)-treated, 10 treated with no-IFN therapies, 17 untreated) and 20 matched healthy controls (HCs) for the putative correlation of the densitometric expression of glucosidase II alpha subunit (GANAB) with clinical/paraclinical parameters and with interferon-induced protein 35 (IFI35). We also assessed the disease progression in terms of the Rio Score (RS) in order to distinguish the responder patients to IFN therapy (RS = 0) from the non-responder ones (RS ≥ 1). We found GANAB to be 2.51-fold downregulated in the IFN-treated group with respect to the untreated one (p < 0.0001) and 3.39-fold downregulated in responder patients compared to the non-responders (p < 0.0001). GANAB correlated directly with RS (r = 0.8088, p < 0.0001) and lesion load (LL) (r = 0.5824, p = 0.0014) in the IFN-treated group and inversely with disease duration (DD) (r = -0.6081, p = 0.0096) in the untreated one. Lower mean values were expressed for GANAB than IFI35 in IFN responder (p < 0.0001) and higher mean values in the non-responder patients (p = 0.0022). Inverse correlations were also expressed with IFI35 in the overall patient population (r = -0.6468, p < 0.0001). In conclusion, the modular expression of GANAB reflects IFI35, RS, DD, and LL values, making it a biomarker of neuroinflammation that is predictive for disease activity and treatment response in MS.

The Age-Related Efficacy of Dimethyl Fumarate and Natalizumab in the Real-World Management of Multiple Sclerosis.

We investigated the comparative age-related efficacy of dimethyl fumarate (DMF) and natalizumab (NTZ) in clinical practice on multiple sclerosis (MS). Research in this area is lacking in the previous literature. In a three-year retrospective and clinical-paraclinical study, we compared 173 DMF patients and 94 NTZ patients with a similar average age (40 years) and disease duration (DD) (10 years). Expanded Disability Status Scale (EDSS) scores were higher in the NTZ group than in the DMF group at 3.5 vs. 2.5, respectively (p = 0.001). However, in both groups, age values correlated with DD (r = 0.42; p < 0.001), EDSS (r = 0.52; p < 0.001) and age at onset (r = 0.18; p < 0.001). Furthermore, age-adjusted Kaplan-Meier curves showed that NTZ-treated subjects maintained a 1.0-3.0 EDSS status score (p = 0.003) more frequently and a 3.5-7.0 score (p = 0.022) significantly less frequently compared with DMF-treated subjects. The EDSS percentage mean difference between NTZ and DMF groups was 81.6%, decreasing inversely with age (r = -0.34; p < 0.001). Finally, high EDSS score values were reached at the age of 39-40 years, regardless of their experimental group. We demonstrated age as a major contributor in disability and response to therapy in current management of MS. Thus, age should be considered in the risk/benefit evaluation in decision making for the disease modifying treatments in MS.

IFP35 Is a Relevant Factor in Innate Immunity, Multiple Sclerosis, and Other Chronic Inflammatory Diseases: A Review.

Discovered in 1993 by Bange et al., the 35-kDa interferon-induced protein (IFP35) is a highly conserved cytosolic interferon-induced leucine zipper protein with a 17q12-21 coding gene and unknown function. Belonging to interferon stimulated genes (ISG), the IFP35 reflects the type I interferon (IFN) activity induced through the JAK-STAT phosphorylation, and it can homodimerize with N-myc-interactor (NMI) and basic leucine zipper transcription factor (BATF), resulting in nuclear translocation and a functional expression. Casein kinase 2-interacting protein-1 (CKIP-1), retinoic acid-inducible gene I (RIG-I), and laboratory of genetics and physiology 2 Epinephelus coioides (EcLGP2) are thought to regulate IFP35, via the innate immunity pathway. Several in vitro and in vivo studies on fish and mammals have confirmed the IFP35 as an ISG factor with antiviral and antiproliferative functions. However, in a mice model of sepsis, IFP35 was found working as a damage associated molecular pattern (DAMP) molecule, which enhances inflammation by acting in the innate immune-mediated way. In human pathology, the IFP35 expression level predicts disease outcome and response to therapy in Multiple Sclerosis (MS), reflecting IFN activity. Specifically, IFP35 was upregulated in Lupus Nephritis (LN), Rheumatoid Arthritis (RA), and untreated MS. However, it normalized in the MS patients undergoing therapy. The considered data indicate IFP35 as a pleiotropic factor, suggesting it as biologically relevant in the innate immunity, general pathology, and human demyelinating diseases of the central nervous system.

Upper gastrointestinal bleeding in COVID-19 inpatients: Incidence and management in a multicenter experience from Northern Italy.

BACKGROUND: COVID-19 patients have an increased susceptibility to develop thrombotic complications, thus thromboprophylaxis is warranted which may increase risk of upper gastrointestinal bleeding (UGIB). Our aim was to evaluate incidence of UGIB and use of upper GI endoscopy in COVID-19 inpatients. METHODS: The medical and endoscopic management of UGIB in non-ICU COVID-19 patients has been retrospectively evaluated. Glasgow Blatchford score was calculated at onset of signs of GI bleeding. Timing between onset of signs of GI bleeding and execution, if performed, of upper GI endoscopy was evaluated. Endoscopic characteristics and outcome of patients were evaluated overall or according to the execution or not of an upper GI endoscopy before and after 24h. RESULTS: Out of 4871 COVID-19 positive patients, 23 presented signs of UGIB and were included in the study (incidence 0.47%). The majority (78%) were on anticoagulant therapy or thromboprophylaxis. In 11 patients (48%) upper GI endoscopy was performed within 24h, whereas it was not performed in 5. Peptic ulcer was the most common finding (8/18). Mortality rate was 21.7% for worsening of COVID-19 infection. Mortality and rebleeding were not different between patients having upper GI endoscopy before or after 24h/not performed. Glasgow Blatchford score was similar between the two groups (13;12-16 vs 12;9-15). CONCLUSION: Upper GI bleeding complicated hospital stay in almost 0.5% of COVID-19 patients and peptic ulcer disease is the most common finding. Conservative management could be an option in patients that are at high risk of respiratory complications.

IFI35 as a biomolecular marker of neuroinflammation and treatment response in multiple sclerosis.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with unpredictable clinical outcome. As such, there is an urgent need to identify biomarkers that can predict the treatment response. Therefore, in an open-label, clinical, paraclinical and molecular prospective study, we assessed 50 interferon (IFN) treated MS patients for Rio Score (RS)/Modified Rio Score (MRS) and densitometric expression of the interferon-induced protein 35 (IFI35), a signal-protein with potential to be clinically relevant in the management of the disease. We found 4.92-fold upregulated IFI35 in IFN-treated MS group respect to healthy controls (p < .0001) and 2.31-fold respect to untreated MS group (p < .0001). Moreover, IFI35 expression profile correlated with RS and MRS rank values (r = -0.6018, p < .0001; r = -0.620, p < .0001), white matter volume (r = -0.5041; p = .0017) and cerebral lesion load (r = -0.5075; p = .0026). Finally, the main proportion of IFN-treated MS patients non-reaching the 65% threshold in IFI35 expression leaved the RS/MRS rank value 0 in a period ranging from 5 to 15 months (p < .0001) from the study entry; instead, all patients that reaching this threshold maintained the RS/MRS value 0 until the study end (p < .0001). In conclusion, the expression level of IFI35 in untreated MS patients highlights a correlation with neuroinflammation. Furthermore, IFI35 expression in IFN-treated MS patients shows a modular correlation between dosing regimes, which is predictive for long-term clinical outcome and drug efficacy.

Progressive familial intrahepatic cholestasis type-3 and multiple sclerosis: lessons from comorbidity.

The comorbidity between multiple sclerosis (MS) and progressive familial intrahepatic cholestasis type-3 (PFIC3) has never been described yet. ABCB4 gene encodes the multidrug resistant protein 3 (MDR3) and its mutations induce PFIC3 as well as intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). We describe the case of a 32-year-old female with MS and PFIC3 who was effectively treated with natalizumab and ursodeoxycholic acid (UCDA), in contrast to glatiramer acetate, dimethylfumarate, and IFNb1a associated with DILI. Our findings clarify the pharmacodynamics of MS therapies and suggest natalizumab plus UDCA as the effective treatment of PFIC3/MS phenotype, unlike the others that should be avoided.