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"Boneschi, M."
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Reliability and validity of the cross-culturally adapted Italian version of the Core Outcome Measures Index
Patient-orientated outcome questionnaires are essential for the assessment of treatment success in spine care. Standardisation of the instruments used is necessary for comparison across studies and in registries. The Core Outcome Measures Index (COMI) is a short, multidimensional outcome instrument validated for patients with spinal disorders and is the recommended outcome instrument in the Spine Society of Europe Spine Tango Registry; currently, no validated Italian version exists. A cross-cultural adaptation of the COMI into Italian was carried out using established guidelines. 96 outpatients with chronic back problems (>3 months) were recruited from five practices in Switzerland and Italy. They completed the newly translated COMI, the Roland Morris disability (RM), adjectival pain rating, WHO Quality of Life (WHOQoL), EuroQoL-5D, and EuroQoL-VAS scales. Reproducibility was assessed in a subgroup of 63 patients who returned a second questionnaire within 1 month and indicated no change in back status on a 5-point Likert-scale transition question. The COMI scores displayed no floor or ceiling effects. On re-test, the responses for each individual domain of the COMI were within one category in 100% patients for “function”, 92% for “symptom-specific well-being”, 100% for “general quality of life”, 90% for “social disability”, and 98% for “work disability”. The intraclass correlation coefficients (ICC
2,1
) for the COMI back and leg pain items were 0.78 and 0.82, respectively, and for the COMI summary index, 0.92 (95% CI 0.86–0.95); this compared well with 0.84 for RM, 0.87 for WHOQoL, 0.79 for EQ-5D, and 0.77 for EQ-VAS. The standard error of measurement (SEM) for COMI was 0.54 points, giving a ‘‘minimum detectable change’’ for the COMI of 1.5 points. The scores for most of the individual COMI domains and the COMI summary index correlated to the expected extent (0.4–0.8) with the corresponding full-length reference questionnaires (
r
= 0.45–0.72). The reproducibility of the Italian version of the COMI was comparable to that published for the German and Spanish versions. The COMI scores correlated in the expected manner with existing but considerably longer questionnaires suggesting adequate convergent validity for the COMI. The Italian COMI represents a practical, reliable, and valid tool for use with Italian-speaking patients and will be of value for international studies and surgical registries.
Journal Article
Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study
Background: Evoked potentials are used in the functional assessment of sensory and motor pathways. Their usefulness in monitoring the evolution of multiple sclerosis has not been fully clarified. Objective: The aim of this longitudinal study was to examine the usefulness of multimodal evoked potential in predicting paraclinical outcomes of disease severity and as a prognostic marker in multiple sclerosis. Methods: Eighty four patients with clinically definite multiple sclerosis underwent Expanded Disability Status Scale (EDSS) and functional system scoring at study entry and after a mean (standard deviation) follow-up of 30.5 (11.7) months. Sensory and motor evoked potentials were obtained in all patients at study entry and at follow-up in 64 of them, and quantified according to a conventional score. Results: Cross-sectionally, the severity of each evoked potential score significantly correlated with the corresponding functional system (0.32
Journal Article
A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood
Some of the aspects of AHC, however, are clearly distinct from FHM, including choreoathetosis, dystonic posturing, and a progressive course associated with mental deterioration. 7 Concerning the possible genetic origin of the disease, only a few familial cases have been described so far, providing evidence to support an autosomal dominant genetic mechanism of transmission. 8, 9 In the first AHC family described, a balanced reciprocal translocation was detected: 46,XY, t(3;9)(p26;q34), thus indicating the first two genomic regions possibly associated with the disease. 8 Subsequently, mitochondrial abnormalities identified in a few sporadic AHC patients suggested the hypothesis, which was however never clearly confirmed, of a mitochondrial dysfunction underlying the pathogenesis of the disease. 10 Key points Alternating hemiplegia of childhood (AHC, MIM 104290) is a rare syndrome, characterised by early onset of episodic hemi- or quadriplegia lasting minutes to days. [...]the AHC mutation involves a highly conserved sequence, DKTGTL, which is the target of the β-aspartyl-phosphorylation reaction during catalysis in all P-type E1-E2-ATPases independently of their cation specificities. 16, 17 According to this, the AHC mutation appears to cause a loss of function effect when transfected in HeLa cells, despite its correct localisation in the plasma membrane.
Journal Article
Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features
The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures
1
. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances
2
,
3
. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (
LGI1
) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of
LGI1
promotes glial tumor progression. We show that the expression pattern of mouse
Lgi1
is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of
LGI1
as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.
Journal Article
Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study
Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for
FHIT
(Fragile Histidine Triad; combined
P
-value 6.74 × 10
−
6
) and followed by variants in
GAPVD1
(GTPase activating protein and VPS9 domains 1; combined
P
-value 5.83 × 10
−5
) and near
ZNF697
(combined
P
-value 8.15 × 10
−5
).
Journal Article
Lifetime and actual prevalence of pain and headache in multiple sclerosis
The aim of the present study is to assess the actual and lifetime frequency of neuropathic (trigeminal neuralgia, Lhermitte’s sign, dysesthesic pain) and somatic (painful muscle spasms and low back pain) pain and headache (tensive headache and migraine) in a cross-sectional sample of 428 consecutive multiple sclerosis (MS) outpatients followed-up in an Italian University MS center over a 3-month period. The impact of demographic and disease-related variables on pain and headache risk is also studied. A semi-structured questionnaire was administered during a face-to-face interview with MS patients and a multivariate logistic regression model is applied to obtain crude and adjusted risk measures. The mean age of the sample was 38.4 years, and female/male ratio was 1.65. The mean disease duration was 9.6 years and the median Expanded Disability Status Scale was 2.0, with most of the patients (74.8%) being affected by the relapsing–remitting form. Lifetime prevalence at the date of examination of at least one type of neuropathic or somatic pain was 39.8% in MS patients, with 58.5% also including headache, while the actual prevalence was 23.8% and 39.9%, respectively. After multivariate analysis, a progressive course of disease was shown to increase the risk of dysesthesic pain and painful muscle spasms, while greater disability was responsible for a higher risk of back pain. L’Hermitte’s sign was more frequent in younger patients, while females had a higher risk of headache. Pain and headache in MS are not negligible symptoms and a neurological examination should not miss the assessment of risk factors for specific types of pain for a more specific and individualized treatment.
Journal Article
A gain-of-function sodium channel β2-subunit mutation in painful diabetic neuropathy
Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in α-subunits of voltage-gated sodium channels (Navs) in patients with painful diabetic peripheral neuropathy. Mutations in proteins that regulate trafficking or functional properties of Navs could expand the spectrum of patients with Nav-related peripheral neuropathies. The auxiliary sodium channel β-subunits (β1–4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Nav. Mutations in β-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in β-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful diabetic peripheral neuropathy and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A—genes encoding sodium channel α-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the β2-subunit. Functional analysis using current-clamp revealed that the β2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the β2-subunit mutation, as evidenced by voltage-clamp analysis, we found a depolarizing shift in the voltage dependence of Nav1.7 fast inactivation and reduced use-dependent inhibition of the Nav1.7 channel.
Journal Article
The use of magnetic resonance imaging in multiple sclerosis: lessons learned from clinical trials
Magnetic resonance imaging (MRI) is an important paraclinical tool for the diagnosis of multiple sclerosis (MS) and for monitoring its disease course. The efficacy of most of the available MS disease-modifying treatments has been tested in clinical trials where MRI-derived quantities served as primary or secondary outcome measures. However, conventional MRI measures (i.e., the number and volume of contrast-enhancing, the volumes of T2-hyperintense and T1-hypointense lesions and the assessment of brain volume changes) are limited in terms of pathological specificity and, as a consequence, are modestly correlated with clinical measures of disease activity and have a modest prognostic value as predictors of MS evolution. In the present review, we discuss the main factors potentially responsible for the so-called ‘clinicaluMRI paradox’ and how modern quantitative MR-based techniques might contribute to, at least partially, overcome it. The lessons learned from MS trials suggest that future applications of MRI to assess MS evolution should rely upon the use of composite measures thought to reflect the various components of the disease, as well as on study protocols specifically designed on the individual trial characteristics.
Journal Article
IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci
A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis:
RGS1
(
P
value=3.55 × 10
−9
),
IL12A
(
P
=3.08 × 10
−8
) and
MPHOSPH9/CDK2AP1
(
P
=3.96 × 10
−8
). The
RGS1
risk allele is shared with celiac disease (CD), and the
IL12A
risk allele seems to be protective for celiac disease. Within the
MPHOSPH9/CDK2AP1
locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator
CDK2AP1
; this effect is seen in both lymphoblastic cell lines (
P
=1.18 × 10
−5
) and in peripheral blood mononuclear cells from subjects with MS (
P
=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.
Journal Article
Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials
Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of G A efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of G A on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of G A on accumulated disability and the potential role of baseline clinical variables as predicto rs of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo -treated subjects and 0.82 in the pooled GA group (P =0.004), indicating an average reductio n in annualized relapse rate of 28%. A bout a one third reductio n of the total number of on-trial relapses was also observed in patients receiving GA (P B-0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P =0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; C I =0.4-0.9; P =0.02). The drug assignment (P =0.004), baseline EDSS score (P =0.02) and number of relapses during the two years prior to study entry (P =0.002) were significant predicto rs of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of G A in reducing relapse rate and disability accumulatio n in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that G A efficacy is not significantly influenced by the patients’ clinical characteristics at the time of treatment initiation.
Journal Article