Multiple sclerosis: natural history, diagnosis and changes in the brain

This article describes the general symptoms, diagnosis and changes in the nervous system in multiple sclerosis. A second article will describe the specific visual symptoms which are believed to be characteristic of the disease.

Ophthalmological manifestations of multiple sclerosis

Optic neuritis, as a result of the formation of demyelination plaques in the optic nerve, is one of the commonest early symptoms of multiple sclerosis. Hence, it is important that optometrists are aware of the symptoms of optic neuritis and of the conditions with which it can be confused. However, only a proportion of patients with optic neuritis will develop the symptoms of multiple sclerosis. The first part of the article describes the symptoms and differential diagnosis of optic neuritis and its relationship with multiple sclerosis. In the second part of the article, the variety of visual changes and symptoms which can be observed in multiple sclerosis patients will be described.

Aptamer-based surface plasmon sensor for thrombin detection

A series of surface plasmonic fibre devices were fabricated using multiple coatings deposited on a lapped section of a single mode fibre and post-fabrication UV laser irradiation processing with a phase mask, producing a surface relief grating structure. These devices showed high spectral sensitivity in the aqueous index regime ranging up to 4000 nm/RIU for wavelength and 800 dB/RIU for intensity. The devices were then coated with human thrombin binding aptamer. Several concentrations of thrombin in buffer solution were made, ranging from 1nM to 1µM. All the concentrations were detectable by the devices demonstrating that sub-nM concentrations may be monitored.

Toward targeted treatments in tuberous sclerosis

Introduction. Tuberous Sclerosis Complex (TSC) is an autosomal-dominant disease caused by the loss of function of the heterodimeric complex hamartin/tuberin due to TSC1/TSC2 gene mutation. The consequent abnormal activation of mammalian target of rapamycin (mTOR), a serine threonine kinase regulating cellular growth, metabolism and proliferation, is responsible for the structural and functional abnormalities observed in TSC. mTOR inhibitors are a class of drugs specifically targeting the mTOR pathway with promising benefits as a specific targeted treatment of the disease. Areas covered. We have reviewed the literature focusing on the role of mTOR inhibitors in treating TSC-related conditions. They are currently approved for subependymal giant cell astrocytomas, renal angiomyolipomas and more recently for lymphangioleiomyomatosis, but a promising role has been shown also in the other clinical manifestation characteristics of TSC, such as cardiac rhabdomyomas, facial angiofibromas and epilepsy. Expert opinion. mTOR inhibition is considered a disease-modifying therapy and the best approach to prevent the progress of the natural history of the disease. For the first time we have the possibility not only to use a biologically targeted treatment, but also to address different manifestations at the same time, thus significantly improving the therapeutic outlook in this complex disease.

The tuberous sclerosis 2000 study:presentation initial assessments and implications for diagnosis and management

Aims: The Tuberous Sclerosis 2000 Study is the first comprehensive longitudinal study of tuberous sclerosis (TS) and aims to identify factors that determine prognosis. Mode of presentation and findings at initial assessments are reported here. Methods: Children aged 0-16 years newly diagnosed with TS in the UK were evaluated. Results: 125 children with TS were studied. 114 (91%) met clinical criteria for a definite diagnosis and the remaining 11 (9%) had pathogenic TSC1 or TSC2 mutations. In families with a definite clinical diagnosis, the detection rate for pathogenic mutations was 89%. 21 cases (17%) were identified prenatally, usually with abnormalities found at routine antenatal ultrasound examination. 30 cases (24%) presented before developing seizures and in 10 of these without a definite diagnosis at onset of seizures, genetic testing could have confirmed TS. 77 cases (62%) presented with seizures. Median age at recruitment assessment was 2.7 years (range:4 weeks-18 years). Dermatological features of TS were present in 81%. The detection rate of TS abnormalities was 20/107 (19%) for renal ultrasound including three cases with polycystic kidney disease, 51/88 (58%) for echocardiography, 29/35 (83%) for cranial CT and 95/104 (91%) for cranial MRI. 91% of cases had epilepsy and 65% had intellectual disability (IQ<70). Conclusions: Genetic testing can be valuable in confirming the diagnosis. Increasing numbers of cases present prenatally or in early infancy, before onset of seizures, raising important questions about whether these children should have EEG monitoring and concerning the criteria for starting anticonvulsant therapy.

On arterial contractility, energetic requirements of the cardiovascular system, and the formation of arterial sclerosis

The aorta has been viewed as a passive distribution manifold for blood whose elasticity allows it to store blood during cardiac ejection (systole), and release it during relaxation (diastole). This capacitance, or compliance, lowers peak cardiac work input and maintains peripheral sanguine irrigation throughout the cardiac cycle. The compliance of the human and canine circulatory systems have been described either as constant throughout the cycle (Toy et al. 1985) or as some inverse function of pressure (Li et al. 1990, Cappelo et al. 1995). This work shows that a compliance value that is higher during systole than diastole (equivalent to a direct function of pressure) leads to a reduction in the energetic input to the cardiovascular system (CV), even when accounting for the energy required to change compliance. This conclusion is obtained numerically, based on a 3-element lumped-parameter model of the CV, then demonstrated in a physical model built for the purpose. It is then shown, based on the numerical and physical models, on analytical considerations of elastic tubes, and on the analysis of arterial volume as a function of pressure measured in vivo (Armentano et al. 1995), that the mechanical effects of a presupposed arterial contraction are consistent with those of energetically beneficial changes in compliance during the cardiac cycle. Although the amount of energy potentially saved with rhythmically contracting arteries is small (mean 0.55% for the cases studied) the importance of the phenomenon lies in its possible relation to another function of the arterial smooth muscle (ASM): synthesis of wall matrix macromolecules. It is speculated that a reduction in the rate of collagen synthesis by the ASM is implicated in the formation of arteriosclerosis. ^

A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.

PURPOSE: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. RESULTS: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. CONCLUSIONS: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.

Vasodilator-Stimulated Phosphoprotein (VASP)-dependent and -independent pathways regulate thrombin-induced activation of Rap1b in platelets

Background: Vasodilator-Stimulated Phosphoprotein (VASP) is involved in the inhibition of agonist-induced platelet aggregation by cyclic nucleotides and the adhesion of platelets to the vascular wall. αIIbβ3 is the main integrin responsible for platelet activation and Rap1b plays a key role in integrin signalling. We investigated whether VASP is involved in the regulation of Rap1b in platelets since VASP-null platelets exhibit augmented adhesion to endothelial cells in vivo.

Methods: Washed platelets from wild type and VASP-deficient mice were stimulated with thrombin, the purinergic receptors agonist ADP, or the thromboxane A2 receptor agonist U46619 and Rap1b activation was measured using the GST-RalGDS-RBD binding assay. Interaction of VASP and Crkl was investigated by co-immunoprecipitation, confocal microscopy, and pull-down assays using Crkl domains expressed as GST-fusion proteins.

Results: Surprisingly, we found that activation of Rap1b in response to thrombin, ADP, or U46619 was significantly reduced in platelets from VASP-null mice compared to platelets from wild type mice. However, inhibition of thrombin-induced activation of Rap1b by nitric oxide was similar in platelets from wild type and VASP-null mice indicating that the NO/cGMP/PKG pathway controls inhibition of Rap1b independently from VASP. To understand how VASP regulated Rap1b, we investigated association between VASP and the Crk-like protein (Crkl), an adapter protein which activates the Rap1b guanine nucleotide exchange factor C3G. We demonstrated the formation of a Crkl/VASP complex by showing that: 1) Crkl co-immunoprecipitated VASP from platelet lysates; 2) Crkl and VASP dynamically co-localized at actin-rich protrusions reminiscent of focal adhesions, filopodia, and lamellipodia upon platelet spreading on fibronectin; 3) recombinant VASP bound directly to the N-terminal SH3 domain of Crkl; 4) PKA-mediated VASP phosphorylation on Ser157 abrogated the binding of Crkl.

Conclusions: We identified Crkl as a novel protein interacting with VASP in platelets. We propose that the C3G/Crkl/VASP complex plays a role in the regulation of Rap1b and this explains, at least in part, the reduced agonist-induced activation of Rap1b in VASP-null platelets. In addition, the fact that PKA-dependent VASP phosphorylation abrogated its interaction with Crkl may provide, at least in part, a rationale for the PKA-dependent inhibition of Rap1b and platelet aggregation.

Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas

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Balancing the demands of two tasks: an investigation of cognitive-motor dual-tasking in relapsing remitting multiple sclerosis

Background: People with relapsing remitting MS (PwRRMS) suffer disproportionate decrements in gait under dual-task conditions, when walking and a cognitive task are combined. There has been much less investigation of the impact of cognitive demands on balance. This study investigated whether: (1) PwRRMS show disproportionate decrements in postural stability under dual-task conditions compared to healthy controls; (2) dual-task decrements are associated with everyday dual-tasking difficulties. In addition, the impact of mood, fatigue and disease severity on dual-tasking were also examined. Methods: 34 PwRRMS and 34 matched controls completed cognitive (digit span) and balance (movement of centre of pressure on a Biosway, on stable and unstable surfaces) tasks under single and dual-task conditions. Everyday dual-tasking was measured using the DTQ. Mood was measured by the HADS. Fatigue was measured via the MFIS. Results: No differences in age, gender, years of education, estimated pre-morbid IQ or baseline digit span between the groups. Compared to healthy controls, PwRRMS showed a significantly greater decrement in postural stability under dual-task conditions on an unstable surface (p=0.007), but not a stable surface (p=0.679). PwRRMS reported higher levels of everyday dual-tasking difficulties (p<0.001). Balance decrement scores were not correlated with everyday dual-tasking difficulties, or with fatigue. Stable surface balance decrement scores were significantly associated with levels of anxiety (rho=0.527, p=0.001) and depression (rho=0.451, p=0.007). Conclusion: RRMS causes difficulties with dual-tasking, impacting balance, particularly under challenging conditions, which may contribute to an increased risk of gait difficulties and falls. The striking relationship between anxiety/depression and dual-task decrement suggests that worry may be contributing to dual-task difficulties.

The influence of the initial state of nutrition on the lifespan of patients with amyotrophic lateral sclerosis (ALS) during home enteral nutrition

Aim: Amyotrophic lateral sclerosis (ALS) is a chronic, neurodegenerative disease, which leads to development of malnutrition. The main purpose of this research was to analyze the impact of malnutrition on the course of the disease and long-term survival. Material and methods: A retrospective analysis has been performed on 48 patients (22 F [45,83%] and 26 M [54,17%], the average age of patients: 66,2 [43-83]) in 2008-2014.The analysis of the initial state of nutrition was measured by body mass index (BMI), nutritional status according to NRS 2002, SGA and concentration of albumin in blood serum. Patients were divided into two groups, depending on the state of nutrition: well-nourished and malnourished. The groups were created separately for each of these, which allowed an additional comparative analysis of techniques used for the assessment of nutritional status. Results: Proper state of nutrition was interrelated with longer survival (SGA: 456 vs. 679 days, NRS: 312 vs. 659 vs. 835 days, BMI: respectively, 411, 541, 631 days, results were statistically significant for NRS and BMI). Concentration of albumin was not a prognostic factor, but longer survival was observed when level of albumin was increased during nutritional therapy. Conclusions: The initial nutrition state and positive response to enteral feeding is associated with better survival among patients with ALS. For this reason, nutritional therapy should be introduced as soon as possible.

Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.