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Biomedical subjects

G Comi

Publications and source records attributed to G Comi.

At least 235 records · Page 13Linked to original sources
PubMed1998

How does brain MRI lesion volume change on serial scans in patients with multiple sclerosis?

Although lesion load changes on conventional T2-weighted brain magnetic resonance imaging (MRI) scans from patients with multiple sclerosis (MS) are used to monitor the effect of treatment, there is no clear definition of how lesion load changes over years according to the lesion load present at a baseline evaluation. In the present study, we evaluated the relationship between lesion load changes over time and lesion load at a baseline evaluation in a group of untreated patients with MS. We scanned nineteen patients on two separate occasions with a mean interval 16.4 months between the two examinations. In each scanning session, a scan with forty contiguous 3-mm-thick axial slices was acquired. We assessed MRI lesion loads using a semi-automated local thresholding technique. Both a linear (p < 0.0001) and a quadratic component (p = 0.0008) of the baseline volume were significant in describing the follow-up volume. The equation to model this finding was as follows: Vf = beta0 Vb + beta1 (Vb)2, where Vf is the lesion volume at follow-up, Vb is the lesion volume at baseline, beta0 = 0.834 (SE = 0.098), and beta1 = 0.014 (SE = 0.003) (mL)(-1). Our data indicate that lesion volume changes detectable on serial brain MRI studies from patients with MS are dependent on the extent of lesion burden present on the baseline MRI scans. This finding has to be considered when planning phase III trials.

Adult↗
PubMed1998

Brain MRI lesion volume measurement reproducibility is not dependent on the disease burden in patients with multiple sclerosis.

We evaluated the potential effect of the lesion burden on the reproducibility of repeated lesion volume (LV) measurements from brain magnetic resonance imaging (MRI) scans of patients with multiple sclerosis (MS). Dual-echo, conventional spin echo brain MRI scans were obtained from 107 patients with MS. On proton density-weighted images, LV was assessed three times by the same raters, using a semi-automated, local thresholding technique for lesion segmentation. Mean LV (MLV) was 16.1 mL (range = 0.7-57.3 mL). The mean intra-observer coefficient of variation (COV) for the three measurement replicates was 2.6% (range = 0.2-7.2%). The intra-observer measurement variance (Var) increased with MLV and the fitted model was Var = 0.00187 MLV1.84. This indicates that LV measurements can be considered as measures whose variances are proportional to the square of their mean values, i.e., these measures have constant COV. Using a semi-automated, local thresholding segmentation technique, the reproducibility of LV measurements from brain MRI scans of patients with MS is not significantly influenced by varying lesion burdens.

Analysis of Variance↗
PubMed1998

Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. Collectively, these mutations account for 11% of MH cases and identify the gene segment 6400-6700 as a mutation hot spot. Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype.

Female↗
PubMed1998

A multi-centre longitudinal study comparing the sensitivity of monthly MRI after standard and triple dose gadolinium-DTPA for monitoring disease activity in multiple sclerosis. Implications for phase II clinical trials.

In this study we assessed the safety, efficacy and cost-effectiveness of the use of triple dose gadolinium-DTPA (Gd) in serial monthly brain MRI of patients with multiple sclerosis, such as could be selected for clinical trials. The number of enhancing lesions, the number of new enhancing lesions and the number of active scans were used to evaluate the sensitivity of the contrast-enhanced MRI to disease activity. The dose of Gd, and the effect of introducing a delay between the contrast injection and the scan were both appraised. Every 4 weeks for 3 months, and in two separate sessions, scans were obtained from 40 patients with relapsing-remitting or secondary progressive multiple sclerosis, 5 min (early) and 20 min (delayed) after a standard dose (0.1 mmol/kg) or triple dose (0.3 mmol/kg) Gd injection. There were 435 enhancing lesions (242 of which were new) on the early standard dose scans, 479 (263 new) on the delayed standard dose, 772 (365 new) on the early triple dose and 827 (404 new) on the delayed triple dose. There were 109 scans revealing active disease on the early standard dose scans, 112 on the delayed standard dose, 119 on the early triple dose and 120 on the delayed triple dose. Statistical simulations indicated that the sample sizes needed for both cross-over and parallel-group trials with similar powers are lower if serial monthly triple dose MRI is used. No side-effects were reported and no significant changes in blood test parameters were found throughout the study. This study shows that the serial use of triple dose Gd is safe, and that it increases the sensitivity of serial monthly enhanced MRI in detecting multiple sclerosis activity significantly. Its use should enable preliminary trials of experimental therapies for multiple sclerosis to be conducted in small patient populations, over a short period of time.

Adult↗
PubMed1998

Metabolic neuropathies.

A large epidemiological study has documented that one-third of diabetic patients have peripheral neuropathy. Diabetes duration, poor glycaemic control, smoking and hypertension are all independent predictors of the incidence of diabetic polyneuropathy. High prevalence of autonomic dysfunctions, both sympathetic and parasympathetic, has been found in patients with nonalcoholic chronic liver disease. The pathogenesis of metabolic neuropathy is unclear; even immunologic factors might play a role in the development of diabetic autonomic neuropathy. No specific treatments are available for these neuropathies. Correction of metabolic derangement is fundamental, as shown by the amelioration of peripheral nerve function obtained after successful simultaneous pancreas-kidney transplantation. The therapeuthic potentials of neurotrophins for the prevention and treatment of diabetic neuropathy have to be confirmed in future studies.

Diabetes Mellitus, Type 1↗
PubMed1998

Use of polymerase chain reaction and restriction enzyme analysis to directly detect and identify Salmonella typhimurium in food.

A primer set of oligonucleotides (Salm 3 and Salm 4) from the invA gene of Salmonellae has been evaluated for the specific detection of Salmonella spp. by the polymerase chain reaction (PCR). This primer set amplified 33 Salmonella serovars but did not amplify 16 non-Salmonella bacteria. Moreover, after PCR amplification, it was possible to identify Salm. typhimurium by restriction enzyme analysis. The PCR-RE method developed could represent a helpful tool for detecting Salmonella spp., and for directly and rapidly identifying Salm. typhimurium in food.

Animals↗
PubMed1998

A highly sensitive and fast non-radioactive method for the detection of polymerase chain reaction products from Salmonella serovars, such as Salmonella typhi, in blood specimens.

A polymerase chain reaction based test was developed for the detection of Salmonella spp. in blood specimens. After amplification of a 389 bp-polymerase chain reaction product from the invA gene, a microtiter plate hybridization assay was performed. The protocol described allowed the detection of six to seven copies of the Salmonella typhi genome, as determined by serial dilutions of DNA from S. typhi. Eighteen blood specimens from artificially infected rats and 22 blood specimens from patients were analyzed to validate the method. Considering that the most frequent Salmonella serovar isolated from blood in case of bacteremia is S. typhi, the polymerase chain reaction-microtiter plate hybridization technique could be used as a novel, rapid diagnostic method for typhoid fever, particularly when standard culture assays are negative.

Animals↗
PubMed1998

A comparison between the sensitivities of 3-mm and 5-mm thick serial brain MRI for detecting lesion volume changes in patients with multiple sclerosis.

In this longitudinal study the authors evaluated the sensitivity of 3-mm and 5-mm magnetic resonance imaging (MRI) of the brain in the detection of lesion load changes over time in multiple sclerosis (MS). The authors also correlated the changes detected with these two techniques with the changes in disability. Eighteen patients with MS underwent two MRI examinations of the brain--one at entrance into the study and one follow-up examination. At both sessions, images with 24 contiguous slices 5 mm thick and another with 40 contiguous axial slices 3 mm thick were consecutively acquired. On the same occasions, the patients' Expanded Disability Status Scale (EDSS) scores were rated. MR images with slices 3 mm thick showed higher lesion loads than those with slices 5 mm thick at both entrance and follow-up examinations (median, 13.4 vs 12.8 ml and 17.5 vs 17.0 ml, respectively; p < 0.0001). The correlation between MRI and EDSS changes was significant for both MRI acquisition schemes (3 mm, r = 0.64; 5 mm, r = 0.59). The data suggest that acquisition of thinner slices does not significantly increase the sensitivity of MRI of the brain in the detection of lesion load changes in MS.

Adult↗
PubMed1998

Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure.

OBJECTIVE: To investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with beta myosin heavy chain (beta MHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure. DESIGN: Molecular analysis of beta MHC and mtDNA gene defects in patients with HCM. SETTING: Cardiovascular molecular diagnostic and heart transplantation reference centre in north Italy. PATIENTS: Four patients with HCM who underwent heart transplantation for end stage heart failure, and after pedigree analysis of 60 relatives, eight additional affected patients and 27 unaffected relatives. A total of 111 unrelated healthy adult volunteers served as controls. Disease controls included an additional 27 patients with HCM and 102 with dilated cardiomyopathy. INTERVENTION: Molecular analysis of DNA from myocardial and skeletal muscle tissue and from peripheral blood specimens. MAIN OUTCOME MEASURES: Screening for mutations in beta MHC (exons 3-23) and mtDNA tRNA (n = 22) genes with denaturing gradient gel electrophoresis or single strand conformational polymorphism followed by automated DNA sequencing. RESULTS: One proband (kindred A) (plus seven affected relatives) had arginine 249 glutamine (Arg249Gln) beta MHC and heteroplasmic mtDNA tRNAIle A4300G mutations. Another unrelated patient (kindred B) with sporadic HCM had identical mutations. The remaining two patients (kindred C), a mother and son, had a novel beta MHC mutation (lysine 450 glutamic acid) (Lys450Glu) and a heteroplasmic missense (T9957C, phenylalanine (Phe)-->leucine (Leu)) mtDNA mutation in subunit III of the cytochrome C oxidase gene. The amount of mutant mtDNA was higher in the myocardium than in skeletal muscle or peripheral blood and in affected patients than in asymptomatic relatives. Mutations were absent in the controls. Pathological and biochemical characteristics of patients with mutations Arg249Gln plus A4300G (kindreds A and B) were identical, but different from those of the two patients with Lys450Glu plus T9957C(Phe-->Leu) mutations (kindred C). Cytochrome C oxidase activity and histoenzymatic staining were severely decreased in the two patients in kindreds A and B, but were unaffected in the two in kindred C. CONCLUSIONS: beta MHC gene and mtDNA mutations may coexist in patients with HCM and end stage congestive heart failure. Although beta MHC gene mutations seem to be the true determinants of HCM, both mtDNA mutations in these patients have known prerequisites for pathogenicity. Coexistence of other genetic abnormalities in beta MHC linked HCM, such as mtDNA mutations, may contribute to variable phenotypic expression and explain the heterogeneous behaviour of HCM.

Adult↗
PubMed1998

Detecting new lesion formation in multiple sclerosis: the relative contributions of monthly dual-echo and T1-weighted scans after triple-dose gadolinium.

In this study, we evaluated the frequency of formation of new lesions on brain magnetic resonance imaging (MRI) from patients with relapsing-remitting multiple sclerosis (MS) and defined the relative contributions of unenhanced and enhanced MRI. Every 4 weeks for 3 months, dual-echo and postcontrast T1-weighted (5 min after the injection of 0.3 mmol/kg gadolinium-DTPA) scans were obtained from 28 patients with relapsing-remitting MS. New lesions were defined as those present on dual-echo and/or postcontrast T1-weighted scans but with no corresponding MRI abnormalities on any of the preceding scans. A total of 111 newly formed lesions were detected during the follow-up on dual-echo and postcontrast T1-weighted scans (i.e., an average of 1.3 lesions per patient per month). Ninety-eight (88%) of such lesions were seen on both dual-echo and postcontrast T1-weighted scans, whilst 13 (12%) were seen only with one of the two techniques: 9 only on dual-echo and 4 only on postcontrast scans. Five of the 98 new lesions seen by both techniques were seen by postcontrast scans 1 month before their appearance on dual-echo scans. Our study suggests that both dual-echo and postcontrast T1-weighted scans are useful to detect newly formed lesions in patients with MS. This is of importance when using MRI to monitor the efficacy of treatments which may halt MS lesion formation.

Adult↗
PubMed1998

A gene therapy approach to treat demyelinating diseases using non-replicative herpetic vectors engineered to produce cytokines.

A successful gene therapy approach in organ-specific autoimmune diseases, such as multiple sclerosis (MS), encompasses the inhibition of the autoreactive T cells or the modification of the target organ cells by the introduction of exogenous 'protective' genes. In MS, an autoimmune disease of the central nervous system (CNS), the inciting autoantigen is still unknown and therefore the isolation of autoreactive T cells may only be inferential. At present, gene therapy approaches in MS should therefore aim to the modification of the target organ. Possible candidate genes to be transferred within the CNS of MS patients are those coding for anti-inflammatory cytokines (i.e. interleukin-4, interleukin-10, transforming growth factor beta) which have been shown to ameliorate demyelinating diseases at least in experimental models. However, a limiting factor for this therapy is the difficulty to reach the CNS. A gene therapy approach using viral vectors able to infect post-mitotic cells, such as those present within the CNS, without inducing toxic reactions, may overcome this limitation. We propose to use non-replicative herpetic vectors, which represent a viable gene-transfer alternative to the classical retroviral and adenoviral vectors. Key advantages are their size, able to accommodate multiple foreign genes, and their ability to infect post-mitotic cells such as those present within the CNS. We first transferred a gene coding for interleukin-4 within the CNS of mice undergoing experimental allergic encephalomyelitis, an animal model for MS, using non-replicative Herpes Simplex Virus type 1-derived vectors. We found that this approach ameliorates the disease course and delays the disease onset. The establishment of this technique to deliver anti-inflammatory cytokines within the CNS using herpetic vectors should clarify the role of individual cytokines in the demyelinating process and allow assessment of whether gene therapy using herpetic vectors is a feasible and safe approach to treat human demyelinating disorders.

Animals↗
PubMed1998

Neurophysiological and cognitive markers of disease evolution in multiple sclerosis.

Both evoked potentials and cognitive tests may provide useful information which cannot be derived from the clinical observation. For this reason, there have been some attempts to use EPs in monitoring the natural history of the disease and in assessing the efficacy of therapeutic trials. However, no conclusion can be derived from the few available data. Although MRI is more sensitive than EPs in revealing new lesions in brain, cerebellum and brainstem, EPs are more sensitive in revealing optic nerve and spinal cord lesions. Moreover, the poor relationship between brain MRI abnormalities and disability has raised the possibility that cognitive evaluation may be an additional sensitive marker of brain involvement over time. Since the gold standard for the assessment of disease activity is uncertain, it is therefore advisable that frequent MRI, EPs and cognitive assessment may integrate clinical outcomes measured by conventional scales, both in the study of the natural disease course and in monitoring clinical trials.

Biomarkers↗
PubMed1998

The effect of cross-talk on MRI lesion numbers and volumes in multiple sclerosis using conventional and turbo spin-echo.

We measured and compared lesion numbers and volumes present on brain magnetic resonance imaging (MRI) scans of patients with multiple sclerosis (MS) acquired with contiguous (scheme A) and interleaved (scheme B) slice acquisition, to evaluate whether there was a gain in sensitivity using the second pattern of acquisition and whether this counterbalanced the doubled acquisition time. Conventional spin-echo (CSE) sequences were performed for eight patients and turbo spin-echo (TSE) sequences for ten. Acquisition scheme B detected 3.8% more lesions than acquisition scheme A (the increase was 3.1% for CSE and 4.5% for TSE). These differences were not statistically significant. No significant difference in lesion numbers was found when different lesion locations were also considered. Lesions volumes were significantly higher when scheme B was used (P = 0.024). This was due to higher lesion volumes on TSE images (P = 0.006), especially on even-numbered slices (P = 0.008). Inter-slice cross-talk has a negligible effect on lesion numbers and volume estimates in MS for CSE sequence, whilst it cannot be neglected when TSE sequences are used to measure MS lesion volume.

Adult↗
PubMed1998

Characteristics of chronic MS lesions in the cerebrum, brainstem, spinal cord, and optic nerve on T1-weighted MRI.

We analyzed the prevalence of severely hypointense lesions on T1-weighted MRI in the brainstem, spinal cord, and optic nerve from 65 patients with MS. About half of 1,274 supratentorial lesions were classified as severely hypointense. Severe hypointensity was not seen in the optic nerve and spinal cord, and in only one of 168 chronic brainstem lesions. Tissue destruction in the brainstem, spinal cord, and optic nerve of MS patients does not usually result in severely hypointense lesions.

Adolescent↗
PubMed1998

Magnetization transfer ratios in multiple sclerosis lesions enhancing after different doses of gadolinium.

We performed serial monthly magnetization transfer (MT) imaging to evaluate whether MS lesions that enhance only after the injection of a triple dose (TD) of gadolinium-DTPA (Gd) have different pathologic characteristics and evolution than those that enhance after the injection of a standard dose (SD). Every 4 weeks for 3 months and in two separate sessions, we obtained T1-weighted scans from 10 patients with relapsing-remitting MS, 5 minutes after SD (0.1 mmol/kg) or TD (0.3 mmol/kg) Gd injection. During each of the first monthly sessions, we obtained MT images and dual-echo scans before Gd injection. We measured the MT ratio (MTR) of newly enhancing lesions on co-registered quantitative MTR images. During the 3-month follow-up, 81 newly enhancing lesions were seen on SD scans. An additional 46 lesions enhanced only on TD scans. The mean (+/- standard deviation) MTR values were 31.4% +/- 8.4% for lesions enhancing after SD and 38.2% +/- 6.0% for lesions enhancing only after TD injection (p < 0.0001). The mean MTR values of lesions seen with both SD (p < 0.00001) and TD (p = 0.002) increased significantly during the follow-up. At each time point during the follow-up, the MTR values of TD lesions were significantly higher than the SD lesions. These results indicate that the enhancing lesion population in MS is heterogeneous and that the tissue damage occurring within lesions enhancing only after TD injection is less severe than in lesions enhancing after the injection of an SD.

Adult↗
PubMed1998

Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis.

OBJECTIVE: This study correlated the extent of abnormalities detected by different magnetic resonance imaging (MRI) techniques [proton density (PD)-weighted, T1-weighted, and magnetization transfer imaging (MTI)] with the overall cognitive, frontal lobe, and memory impairments in patients with MS. PATIENTS: There were 30 clinically definite MS patients, with different disease courses. EXCLUSION CRITERIA: psychoactive/steroid treatments, mood disorders, acute relapse phase. MAIN OUTCOME MEASURES: Neuropsychological test results. Total (TLL) and frontal (FLL) lesion loads assessed from PD-weighted, T1-weighted (22 patients), and MTI (22 patients) MRI scans. Average lesion MT ratios (MTR) and analysis of the MTR histograms from brain tissue axial slabs on MTI scans. RESULTS: Patients with frontal lobe deficits (n=15) or memory impairment (n-17) had a higher TLL on PD scans (p=0.04 and p=0.01, respectively). Patients with frontal lobe deficits had higher FLL on PD scans (p=0.01) and TLL on MTI (p=0.03) scans. No significant relationships between the extent of T1-weighted lesion loads and the presence of any neuropsychological impairment. Mean MTR of both MS lesions and whole brain tissue was lower in patients with frontal lobe impairment (p=0.04). MRI lesion loads correlated significantly with some neuropsychological test scores. CONCLUSIONS: Lesion loads on PD-weighted MRI and MTI-derived measures are associated with cognitive decline in MS patients. Overall macroscopic and microscopic brain damage is more important than the corresponding regional brain disease in determining deficits of selective cognitive domains.

Adult↗
PubMed1998

Benign versus secondary-progressive multiple sclerosis: the potential role of proton MR spectroscopy in defining the nature of disability.

PURPOSE: We determined the clinical utility of proton MR spectroscopy in defining the extent of disability in benign versus secondary-progressive multiple sclerosis (MS). METHODS: Thirty patients with clinically definite MS, including 16 patients with benign MS and 14 with secondary-progressive MS, and a group of 13 healthy volunteers were studied with combined stimulated-echo acquisition mode proton MR spectroscopy and MR imaging (all patients received contrast material). RESULTS: Acute enhancing lesions of benign and secondary-progressive MS were characterized by a reduction in N-acetylaspartate (NAA)/choline and NAA/creatine and an increase in inositol compounds/creatine as compared with normal white matter. Such variations were also detected in chronic unenhancing lesions in patients with secondary-progressive MS, although they were not found in chronic unenhancing lesions in patients with benign MS. Chronic lesions of the two forms of the disease have significative differences in NAA and inositol signals. CONCLUSION: Proton MR spectroscopy is able to show metabolic changes occurring in the white matter of patients with MS. Such changes differ according to the phase (acute versus chronic) and the clinical form (benign versus secondary-progressive) of the disease.

Adult↗