Clinical and biological predictors of Cladribine effectiveness in Multiple Sclerosis: A real-world, single Centre study considering a two-year interval from year-2 dosing.

OBJECTIVES: Cladribine tablets (CLAD) for adult patients with highly active relapsing multiple sclerosis (RMS) have been available in Italy since 2018. We aimed to assess predictors of no-evidence-of-disease-activity-3 (NEDA-3) status after 24 months of the last dose of CLAD. RESULTS: We included 88 patients (70.5% female, mean age at CLAD start 35.4 ± 11.4). Eighteen patients were treatment naïve, 48 switched to CLAD from a First line Disease Modifying Drug (DMD), and 22 from Second line DMDs. All patients were observed for a median follow-up time of 2.4 (1-4) years after the last dose of CLAD. Forty-nine patients (55.7%) showed NEDA at the last available follow-up. Naïve patients (p = 0.001), those with a lower number of previous DMDs (p < 0.001) and, even though not significantly, those switching from first line DMDs (p = 0.069) were more likely NEDA3 at the last available follow-up. In a subgroup of 30 patients (34%), Serum Light Neurofilaments (sNFL) levels showed a decrease from baseline to the 24 months of follow-up, statistically significant from baseline to the sixth month, and from the first to the second year detection. sNFL levels at 12th month showed a strong inverse correlation with the time to NEDA3 loss. CONCLUSIONS: Our experience provides information for the 2-years after the last dose of CLAD, confirming a higher effectiveness of CLAD when placed early in the treatment algorithm. Given the ongoing expansion of the therapeutic landscape in MS, sNfL could support individualized decision-making, used as blood-based biomarker for CLAD responses in clinical practice.

Plasma pentraxin 3 in idiopathic inflammatory myopathies: a possible new biomarker of disease activity.

Pentraxin-3 (PTX3) is a component of humoral innate immunity with essential functions both in promotion and resolution of inflammation. We aimed to study the PTX3 in the plasma and in the muscle of patients with idiopathic inflammatory myopathies (IIM) and whether PTX3 may correlate with disease activity. Plasma PTX3 levels were assessed in 20 patients with IIMs, 10 dermatomyositis (DM), and 10 polymyositis (PM), compared to 10 patients with rheumatoid arthritis (RA) and 10 healthy donors (HDs) aged, sex, and body mass index matched. Disease activity in IIMs was assessed by Myositis Disease Activity Assessment Visual Analog Scale (MYOACT), while disease activity score on 28 joints (DAS28) was used for RA patients. Muscle histopathology and immunohistochemical (IHC) analyses were also performed. Mean plasma PTX3 levels were significantly higher in IIM patients than HDs (518 ± 260 pg/ml vs. 275 ± 114 pg/ml, P = 0.009). Linear regression analysis adjusted for age, sex, and disease duration showed a direct correlation between PTX3 and CPK levels (ß: 0.590), MYOACT (ß: 0.759), and physician global assessment of disease activity (ß: 0.832) in IIMs. No association between PTX3 levels and DAS28 was found in RA. Global PTX3 pixel fraction was higher in IIM than HDs muscle, but a lower PTX3 expression was found in perifascicular areas of DM and in myofibers with sarcolemmal staining for membrane attack complement. PTX3 plasma levels were increased in IIMs and correlated with disease activity suggesting a possible role as biomarker of disease activity. PTX3 showed a different distribution in DM or PM muscle.

Ptosis in childhood: A clinical sign of several disorders: Case series reports and literature review.

Blepharoptosis (ptosis) is a common but often overlooked sign that may serve as a sign/manifestation of other conditions, ranging from a mild and purely cosmetic presentation to a severe and occasionally progressive disorder. Ptosis may show an acute onset or may manifest as a chronic disorder. Its presentation may vary: unilateral versus bilateral, progressive versus non-progressive, isolated versus complex which occurs in association with other symptoms, and congenital versus acquired (often concomitant with neuromuscular disorders).Congenital ptosis includes the isolated type-the congenital cranial dysinnervation disorders, which are further, distinguished into different subtypes such as Horner syndrome (HS), and ptosis as a sign/manifestation of various congenital malformation syndromes.In this article, we review the primary causes of ptosis occurring in childhood, and its various clinical presentations, including a short report on selected cases observed in our institution: a classical isolated familial ptosis comprising 14 members over 5 generations, 3 sibling with isolated congenital ptosis who in addition suffered by episodes of febrile seizures, a patient with Duane retraction syndrome who presented congenital skin and hair anomalies, and a girl with HS who showed a history of congenital imperforate hymen. A flowchart outlining the congenital and acquired type of ptosis and the clinical approach to the management and treatment of children with this anomaly is reported.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.

Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders.

In the United States, 1.1-1.5% of children have been diagnosed with autism spectrum disorders (ASD), corresponding to a 30% increase in incidence and prevalence. Social and communication impairments are the main signs and symptoms of ASD, and currently available medications have been ineffective in reducing these core deficits. Observational studies have indicated that children with ASD tend to show improved cognition and behavior after febrile illness, which is associated with alteration of metabolic pathways, leading to cellular stress responses and increased expression of heat shock proteins (Hsps). Sulforaphane and hydroxytyrosol, phytochemicals derived from cruciferous vegetables and extra virgin olive oil, respectively, can induce metabolic effects in cellular stress responses that are similar to those produced by fever. Thus, modulation of endogenous cellular defense mechanisms may be an innovative approach for therapeutic intervention in ASD and other disorders associated with neuroinflammation and neurodegeneration. This Review introduces the hormetic dose-response concept and presents possible mechanisms and applications for neuroprotection. We address the emerging role of Hsps in the neuroprotective network of redox stress-responsive mechanisms and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of ASD. We argue that such research findings must be approached with pragmatism and prudence. It is vital to capitalize on recent and ongoing investments in brain science research and to refine neuroscientific knowledge and capability for more accurate diagnosis and safe, effective, and ethically sound treatment of ASD and other neuropsychiatric spectrum disorders. © 2016 Wiley Periodicals, Inc.

Bilateral hand squamous-cells carcinoma in patient affected with non-Hodgkin lymphoma. Case report and literature review.

BACKGROUND: Squamous-cell skin cancer is the most frequent tumor in the hand. It occurs on sun-damaged skin, especially in lightskinned individuals with a long history of chronic sun exposure. CASE REPORT: We describe a case of bilateral hand squamous-cell carcinoma in a elderly patient affected with non-Hodgkin's lymphoma, who underwent several non-successful surgical treatment, radiotherapy and at the least, amputation of right hand for rapid clinical evolution after radiotreatment. Available literature on the subject has been reviewed. RESULTS: In our case, after several non-successful treatment, elective amputation at the distal third of forearm was performed. We reviewed 56 items including books, original articles, reviews, cases report. CONCLUSIONS: Current evidence on treatment of hand squamouscells carcinoma is to perform a first radical surgical treatment in order to avoid recurrence/metastasis and to achieve a safer level of amputation thus increasing the surface area of healthy tissue available for eventually subsequent reconstruction/prosthesization.

Caustic burn caused by intradermal self administration of muriatic acid for suicidal attempt: optimal wound healing and functional recovery with a non surgical treatment.

BACKGROUND: Caustic burns are burns of third and fourth degree caused by strong acids or strong bases. Muriatic acid is often used for suicidal attempt by ingestion. We describe a case of a caustic skin lesion caused by intravenous failed attempt of suicide by injection of Muriatic acid in a woman affected with bipolar-syndrome. Generally, caustic burns are treated by cleansing, escarectomy and coverage with skin grafts. CASE REPORT: We treated the patient with a non invasive technique with collagenase and hyaluronic acid sodium salt cream (Bionect start®), hyaluronic acid-based matrix (Hyalomatrix®) and Vacuum-Assisted Closure (VAC) Therapy®. RESULTS: We obtained complete healing in 6 weeks. CONCLUSIONS: Combined use of non invasive techniques seems to ensure only advantages for both the patients and the Health System. It reduces health care costs and risks for the patients such as nosocomial infections. Patient's compliance is high, as its quality of life. Complete healing of the wound is fast and recovery of function is full.

Postoperative care in finger replantation: our case-load and review of the literature.

OBJECTIVE: Technical success of a finger replantation depends on several factors such as surgical procedure, type of injury, number of segments amputated, amputation level and individual patient factors. Among early complications that can occur in this type of surgery the onset of venous or arterial thrombosis is the most dreaded. Local irrigating solutions, oral and intravenous anticoagulants, thrombolytic agents, plasma expanders, vasodilating, and antiaggregant drugs are routinely used in patients undergoing microvascular procedures, but currently there is only a non-standardized practice based on anecdotal personal experience. MATERIALS AND METHODS: The aim of our study is to review selected literature relating to perioperative therapy in microsurgical digital replantation. We also report our case-load of 16 patients with finger avulsion describing our particular protocol for postoperative anticoagulation and restoration of fluid and electrolyte balance. RESULTS: Following our daily pharmacological protocol, the postoperative course of the replanted fingers was uneventful. The survival rate for finger replantations performed was 100% (n = 16) with no need for surgical revisions. CONCLUSIONS: The association Dextran-40/Heparin/fluids in the proposed standardized pro-weight pharmacological protocol is an optimal postoperative prophylactic/therapeutic plan to reduce the incidence of endovascular thrombosis after replantation, so ensuring high rate of success in microvascular surgery.

The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features.

Spinal neurofibromatosis (SNF) is a related form of neurofibromatosis 1 (NF1), characterized by bilateral neurofibromas (histologically proven) of all spinal roots (and, eventually, of all the major peripheral nerve branches) with or without other manifestations of classical NF1. By rigorous application of these criteria to the 98 SNF cases published, we developed: (i) a cohort of 49 SNF patients (21 males and 28 females; aged 4-74 years]: 9 SNF families (21/49), 1 mixed SNF/NF1 family (1/49) and 27 of 49 sporadic SNF patients (including 5 unpublished patients in this report); and (ii) a group of 49 non-SNF patients including: (a) 32 patients with neurofibromas of multiple but not all spinal roots (MNFSR): 4 mixed SNF/MNFSR families (6/32); (b) 14 patients with NF1 manifestations without spinal neurofibromas, belonging to SNF (8/49) or MNFSR families (6/32); (c) 3 patients with neurofibromas in one spinal root. In addition to reduced incidence of café-au-lait spots (67% in SNF vs 56% in MNFSR), other NF1 manifestations were less frequent in either cohort. Molecular testing showed common NF1 gene abnormalities in both groups. The risk of developing SNF vs NF1 was increased for missense mutations [p = 0.0001; odds ratio (OR) = 6.16; confidence interval (CI) = 3.14-13.11], which were more frequent in SNF vs MNFSR (p = 0.0271).

Cerebrospinal fluid neurofilament tracks fMRI correlates of attention at the first attack of multiple sclerosis.

BACKGROUND: Identifying markers of cognitive dysfunction in multiple sclerosis (MS) is extremely challenging since it means supplying potential biomarkers for neuroprotective therapeutic strategies. OBJECTIVE: The aim of this study is to investigate the relationship between fMRI correlates of attention performance and cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels in patients with clinically isolated syndrome (CIS) suggestive of MS. METHODS: Twenty-one untreated, cognitively preserved CIS patients underwent BOLD-fMRI while performing the Variable Attentional Control (VAC) task, a cognitive paradigm requiring increasing levels of attentional control processing. CSF NFL was assessed by ELISA technique. SPM8 random-effects models were used for statistical analyses of fMRI data (p<0.05 corrected). RESULTS: Repeated-measures ANOVA on imaging data showed an interaction between attentional control load and NFL levels in the right putamen. At the high level of attentional control demand CIS patients with "low NFL levels" showed greater activity in the putamen compared with subjects with "high NFL levels" (p=0.001). These results are independent of cognitive impairment index. CONCLUSIONS: Our findings suggest a relationship between CSF NFL levels and load-dependent failure of putaminal recruitment pattern during sustained attention in CIS and suggest a role of CSF NFL as a marker of subclinical abnormality of cognitive pathway recruitment in CIS.

Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To evaluate whether cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels could predict the time to generalization (TTG) in amyotrophic lateral sclerosis (ALS). METHODS: Cerebrospinal fluid NFL levels of 37 cases of sporadic ALS were measured and the time of symptom spreading from spinal or bulbar localization to both (TTG) was evaluated in all patients. RESULTS: Kaplan-Meier analysis showed a short TTG in patients with high NFL levels (log-rank test chi-squared = 19.4, P < 0.0001). In a multivariate regression model patients with NFL levels above the median had an eight-fold higher risk of generalization (adjusted hazard ratio 7.9, 95% confidence interval 2.9-21.4, P < 0.0001) compared with those with NFL levels below the median. CONCLUSIONS: This study shows that in sporadic ALS NFL, a marker of neurodegeneration, is correlated with TTG, a clinical intermediate parameter of survivorship.

Gross anatomical study of the nerve supply of genitourinary structures in female mongrel hound dogs.

Anatomical variations in lumbosacral plexus or nerves to genitourinary structures in dogs are under described, despite their importance during surgery and potential contributions to neuromuscular syndromes. Gross dissection of 16 female mongrel hound dogs showed frequent variations in lumbosacral plexus classification, sympathetic ganglia, ventral rami input to nerves innervating genitourinary structures and pudendal nerve (PdN) branching. Lumbosacral plexus classification types were mixed, rather than pure, in 13 (82%) of dogs. The genitofemoral nerve (GFN) originated from ventral ramus of L4 in 67% of nerves, differing from the expected L3. Considerable variability was seen in ventral rami origins of pelvic (PN) and Pd nerves, with new findings of L7 contributions to PN, joining S1 and S2 input (23% of sides in 11 dogs) or S1-S3 input (5%), and to PdN, joining S1-S2, unilaterally, in one dog. L7 input was confirmed using retrograde dye tracing methods. The PN also received CG1 contributions, bilaterally, in one dog. The PdN branched unusually in two dogs. Lumbosacral sympathetic ganglia had variant intra-, inter- and multisegmental connectivity in 6 (38%). Thus, the anatomy of mongrel dogs had higher variability than previously described for purebred dogs. Knowledge of this variant innervation during surgery could aid in the preservation of nerves and reduce risk of urinary and sexual dysfunctions.

Otoplasty for prominent ears deformity.

OBJECTIVE: Prominent ears are a common congenital deformity of the external ear, derived from a combination of defects in the antihelix and concha. The majority of cases are treated surgically, but one of major difficulties associated with otoplasty regards the achievement of lasting aesthetic results. With the present study we propose an effective combination of four surgical techniques of cartilage reshaping with the ultimate goal of creating a new stable antihelical fold. PATIENTS AND METHODS: Forty-one patients with prominent ears were involved prospectively. The subjects (16 male and 25 female) ranged in age from 6 to 43 years, with a mean age of 12 years. All patients underwent to the same surgical procedure and we performed softening and reshaping of the antihelix adopting the consecutive use of four surgical techniques: hemitransfixing microincisions, scoring, squeezing and posterior mattress suture fixation. RESULTS: Total number of ears that underwent surgery was 71. The mean postoperative follow-up period was 2 years. The mean postoperative change of protrusion was 7.96 mm referring to the superior cephaloauricular distance, while it was 12.18 mm considering the middle cephaloauricular distance. No patient developed complications or recurrence. CONCLUSIONS: The proposed surgical procedure for otoplasty resulted in endurance of auricular appearance and symmetry with high success rate and low morbidity.

Nicotinic receptor subtypes mediating relaxation of the normal human clasp and sling fibers of the upper gastric sphincter.

BACKGROUND: Proper function of the gastro-esophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions and the decreased tone during transient lower esophageal sphincter relaxations. METHODS: We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastro-esophageal reflux disease or histologic evidence of Barrett's esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re-exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re-exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine. KEY RESULTS: 100 µM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4ß2 subunits are also eliminated because choline acts as an agonist and dihydro-beta-erythroidine is ineffective. CONCLUSIONS & INFERENCES: Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3ß4ß2, α2ß4, or α4ß4 subunits.

Brain ultrasound features in multiple births due to spontaneous conception compared with assisted reproductive techniques: a cross-sectional, population-based study.

AIM: Multiple pregnancies from spontaneous conception and obtained by assisted reproductive techniques (ART) are associated with a disproportionate share of complications compared with natural singleton pregnancies. The outcome of multiple pregnancies obtained by ART is still the subject of controversial opinions in the medical literature as they are associated with increased rates of perinatal complications, and perinatal mortality, as well as maternal complications. Aim of this study was to determine whether there are differences between these two groups of infants. METHODS: We examined the imaging findings by means of brain ultrasound (performed at birth and sequentially up to their 6th month of age) in a cohort of 296 twins and triplets born following different techniques of assisted fertilization (63 pregnancies; 119 neonates) vs. spontaneous conception (94 pregnancies; 177 neonates). RESULTS: We did record, by means of X square corrected test, statistically significant differences (P=0.002) between the two populations at birth in the number of normal ultrasound scans (ART

Enhanced nicotinic receptor mediated relaxations in gastroesophageal muscle fibers from Barrett's esophagus patients.

BACKGROUND: Increased nicotinic receptor mediated relaxation in the gastroesophageal antireflux barrier may be involved in the pathophysiology of reflux. This study is designed to determine whether the defects we previously identified in gastroesophageal reflux disease patients in- vivo are due to abnormalities of the gastric sling, gastric clasp, or lower esophageal circular (LEC) muscle fibers. METHODS: Muscle strips from whole stomachs and esophagi were obtained from 16 normal donors and 15 donors with histologically proven Barrett's esophagus. Contractile and relaxant responses of gastric sling, gastric clasp, or LEC fibers were determined to increasing concentrations of carbachol and to nicotine after inducing maximal contraction to bethanechol. Muscarinic receptor density was measured using subtype selective immunoprecipitation. KEY RESULTS: Barrett's esophagus gastric sling and LEC fibers have decreased carbachol-induced contractions. Barrett's esophagus sling fibers have decreased M2 -muscarinic receptors and LEC fibers have decreased M3 receptors. Relaxations of all three fiber types are greater in Barrett's esophagus specimens to both high carbachol concentrations and to nicotine following bethanechol precontraction. The maximal response to bethanechol is greater in Barrett esophagus sling and LEC fibers. CONCLUSIONS & INFERENCES: The increased contractile response to bethanechol in Barrett's specimens indicates that the defect is likely not due to the smooth muscle itself. The enhanced nicotinic receptor mediated response may be involved in greater relaxation of the muscles within the high-pressure zone of the gastroesophageal junction during transient lower esophageal sphincter relaxations and during deglutitive inhibition and may be involved in the pathophysiology of gastroesophageal reflux disease.