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Biomedical subjects

G Izquierdo

Publications and source records attributed to G Izquierdo.

At least 19 recordsLinked to original sources
PubMed2005

SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects motor neurons. It is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. An SMN2 dosage method was applied to 45 patients with the three SMA types (I-III) and to four pairs of siblings with chronic SMA (II-III) and different phenotypes. Our results confirm that the SMN2 copy number plays a key role in predicting acute or chronic SMA. However, siblings with different SMA phenotypes show an identical SMN2 copy number and identical markers, indicating that the genetic background around the SMA locus is insufficient to account for the intrafamilial variability. In our results, age of onset appears to be the most important predictor of disease severity in affected members of the same family. Given that SMN2 is regarded as a target for potential pharmacological therapies in SMA, the identification of genetic factors other than the SMN genes is necessary to better understand the pathogenesis of the disease in order to implement additional therapeutic approaches.

Adult↗
PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗
PubMed2004

Production and biochemical characterization of the recombinant Boophilus microplus Bm95 antigen from Pichia pastoris.

The new antigen Bm95 from the cattle tick Boophilus microplus was recently isolated, cloned and expressed in the methylotrophic yeast Pichia pastoris. The recombinant protein has shown to induce protection in cattle against infestations of B. microplus under controlled and production conditions. In this paper we report the production and large-scale purification of the Bm95 protein, following a simple and cost-effective process. The antigen was obtained highly aggregated, forming particles ranging from 26 to 30 nm and with purity higher than 80%. The process yield was 0.55 g of pure Bm95 protein per liter of culture. The 98% of the primary structure of the recombinant protein was verified by mass spectrometry. Three amino acid changes in comparison with the sequence deduced from cDNA were detected by LC-MS/MS. The antigen was also obtained N-glycosylated, as previously reported for heterologous protein expression in P. pastoris.

Amino Acid Sequence↗
PubMed2004

[Opsoclonus secondary to encephalopolyradiculoneuritis due to Mycoplasma pneumoniae].

Opsoclonus is characterized by sudden onset of arrhythmic, multidirectional chaotic eye movements, generally associated with a parainfectious or paraneoplasic condition. Opsoclonus is a rare manifestation with no known link with infection by Mycoplasma pneumoniae. We present a case of a 23 year old male patient who presented fever, myalgia, vomiting, respiratory failure, opsoclonus and symmetric flaccid tetraparesis with important lower limb muscle atrophy. Serology and seroreversion for M. pneumoniae were both positive. This case illustrates the possibility that M. pneumoniae may produce a predominantly neurological disease and the need to include this infection in the differential diagnosis of opsoclonus, or polyradiculoneuritis.

Adult↗
PubMed2004

[Multifocal motor neuropathy with conduction blocks and prurigo nodularis. A paraneoplastic syndrome in a patient with non-Hodgkin B-cell lymphoma?].

Multifocal motor neuropathy with conduction blocks (MMNCB) is a peripheral demyelinating neuropathy. The etiology of this disease is unknown, but an autoimmune origin is postulated. Prurigo nodularis (PN), a chronic dermatosis also having an unknown etiology and many peripheral neuropathies of different nature are associated to hematological tumors. We have found no cases in the literature in which MMNCB was presented as a paraneoplastic syndrome of a non-Hodgkin B-cell type lymphoma (NHL-B). We present the case of a 67 year old man who simultaneously developed PN and MMNCB in upper limbs and who was diagnosed of a NHL-B 19 months later. We raise the hypothesis that both prurigo and neuropathy are a paraneoplastic syndrome for lymphoma with a possible common autoimmune pathogenic mechanism.

Aged↗
PubMed2003

Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study.

OBJECTIVE: To evaluate the efficacy and safety of IFNbeta-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing-remitting multiple sclerosis (MS). METHODS: In this multicenter, open-label, prospective clinical trial, 96 patients with relapsing-remitting MS received IFNbeta-1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. RESULTS: IFNbeta-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNbeta-1a treatment was well tolerated. CONCLUSION: This study confirms and extends the beneficial clinical profile for IFNbeta-1a in relapsing MS.

Adolescent↗
PubMed2003

[HIV related Foix-Chavany-Marie syndrome].

Automatic-voluntary motor dissociation of the face and lower cranial nerves of brainstem is the hallmark of Foix-Chavany-Marie syndrome (biopercular syndrome). It is commonly caused by ischemic strokes. We present a biopercular syndrome associated with HIV. A 41 year old female who presents a progressive automatic- voluntary motor dissociation of face and lower cranial nerves with later involvement of limbs. She was immunodepressed as a result of HIV. MRI showed bilateral lesions in opercular areas and ventrolateral thalamic nucleus, likely as a result of retrograde neuronal degeneration. Automatic-voluntary dissociation occur after biopercular lesions with sparing of motor pathway proceeding from the cingulate cortex.

Adult↗
PubMed2002

Intrathecal IgG synthesis: marker of progression in multiple sclerosis patients.

OBJECTIVES: We study the power of IgG synthesis value as a marker of disease activity in multiple sclerosis (MS). MATERIAL AND METHODS: Link index was calculated in 202 MS patients. Time between first, second and third attack and progression index (PI) were compared in patient with normal (NLI) high (HL) or very high Link index (VHLI). RESULTS: Secondary progressive (SP) patients had a higher LI than relapsing-remitting (RR) and primary progressive (PP) courses (1.10 +/- 0.5 for SP vs 0.86 +/- 0.5 for RR and 0.81 +/- 0.5 for PP, P=0.01 and 0.03, respectively). Having a HLI in MS RR and SP patients has no time effect in the development of the second and third attack. PI was higher in patients with VHIL (0.67 +/- 0.7) vs patients with NLI (0.42 +/- 0.4, P=0.008) and with HLI (0.39 +/- 0.3, P=0.001). CONCLUSIONS: This study confirmed that LI is a good marker of subsequent progression of MS.

Adult↗
PubMed2002

[Lhermitte's sign].

Besides Babinski's, Lhermitte's sign is likely the eponym mostly used in the neurological literature. We review here the history of this eponym as well as recent advances on its pathophysiology and treatment. Lhermitte's phenomenon is, on one hand, a symptom as it is spontaneously explained by patients, and, on the other hand, a sign as it may be triggered by flexion of the nape. Initially described after head and cervical spine trauma, firstly by Marie and then by Babinski, it was Jean Lhermitte who recognized on it an etiological specificity, namely, a demyelinating sign of cervical spinal posterior cords. He also made a pathophysiological interpretation of the phenomenon, namely, a stretching of posterior cords during flexion of the neck. All authors agree that this phenomenon is more common in multiple sclerosis, although it has been descibed in many other conditions. The history of how this sign was hatched, whose pathophysiology remains a mystery, is fascinating. And it is fascinating the fact that patients compare the phenomenon with a current, especially if we bear in mind that few people may have suffered an electrocution, mainly in that time when just a few ones could actually enjoy domestic electricity.

Cervical Vertebrae↗
PubMed2001

Association of a CA repeat polymorphism upstream of the Fas ligand gene with multiple sclerosis.

We have analyzed a CA repeat polymorphism localized 46-kb upstream of the Fas ligand gene in Spanish and American populations that include 139 healthy controls and a cohort of 177 unrelated relapsing and remitting multiple sclerosis (MS) patients. The MS patients consisted of two groups, one with a family history of MS and one without. The frequency of the 13 CA repeats (allele B) was lower (p=0.01) in MS patients than in controls, 0.45 and 0.55 respectively. The odds ratio (BB vs. AB/AA) for MS patients vs. healthy controls was 0.51 (95% CI 0.3-0.9; p=0.01). The odds ratio (BB vs. AB/AA) for MS patients extracted from multiply affected families vs. healthy controls was 0.22 (95% CI 0.07-0.62; p=0.002). The HLA DRB1*1501-DQB1*0602 haplotype is associated with B allele with a relative frequency higher than A allele (0.52 and 0.48 in patients vs. 0.68 and 0.32 in controls). The results suggest that chromosomes with B allele have a genetic background that reduces susceptibility to MS, particularly in the familial forms.

Alleles↗
PubMed2001

Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.

Mutations in the Kritl gene have been recently discovered as the cause of hereditary cerebral cavernous angioma. We sought the possibility that de novo, noninherited mutations of Kritl also cause cavernous angioma. A patient with two cerebral malformations carries a heterozygous deletion of two base pairs (741delTC) in exon VI of the Kritl gene. The deletion initiates a frameshift mutation that, 23 amino acids downstream, encodes a TAA stop triplet replacing a CAT triplet of histidine at exon VII (H271X). Magnetic resonance images of the parents were normal, neither parent carries the 741delTC mutation, and both bear the wild-type sequence of exon VI. These findings document a de novo germline mutation in Kritl gene that causes cerebral cavernous malformations.

Brain Neoplasms↗
PubMed2000

Molecular analysis of Boophilus spp. (Acari: Ixodidae) tick strains.

Boophilus spp. (Acari: Ixodidae) parasitize cattle and other farm and wild animals in tropical and subtropical regions of the world. Ticks belonging to the genus Boophilus have undergone evolutionary processes associated with habitat adaptation following biogeographical separation, resulting in strains with marked morphological differences. We have characterized at the molecular level B. microplus strains from Latin America and Australia, employing sequences derived from the bm86 coding region, an intron located within the bm86 gene, and DNA short tandem repeats (STR). A B. annulatus strain was employed for comparison. The results indicated that variation within the bm86 coding region is higher between B. microplus strains than between some B. microplus strains and B. annulatus. The sequence of the intron was not informative for phylogenetic analysis, varying among individuals of the same strain. Two STRs were identified in B. microplus (STRs BmM1 and BmM2) and one in B. annulatus (STR Ba1). Southern hybridization experiments with STRs BmM1 and BmM2 as a probe revealed the prevalence of dispersed moderately repeated DNA in the genome of B. microplus. The analysis of polymorphism at STR locus BmM1 evidenced differences within and between populations of B. microplus. These results support at the molecular level the existing differences between B. microplus strains and suggest tools to characterize these populations.

Animals↗
PubMed2000

Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients.

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.

Adult↗
PubMed2000

Serum endothelial adhesion molecules levels correlate with lesion burden in multiple sclerosis patients treated with interferon beta-1b.

The levels of serum-soluble intracellular adhesion molecule-1 and soluble endothelial-leukocyte adhesion molecule-1, and the Gadolinium-enhanced T1-weighted MRI were studied in a group of patients with relapsing-remitting multiple sclerosis treated with interferon beta-1b and compared to a non-treated control group. The levels of serum-soluble intracellular adhesion molecule-1 and soluble endothelial-leukocyte adhesion molecule-1 increased, after three months treatment, as compared to baseline and the non-treated MS patients. A significant correlation was found in the treated group between serum-soluble endothelial-leukocyte adhesion molecule-1 and the lesion area in the Gadolinium-enhancing (T2 weighted scan) MRI.

Adult↗
PubMed2000

Interferon beta-1b treatment in patients with relapsing--remitting multiple sclerosis under a standardized protocol in Spain.

OBJECTIVE: A protocol system is being used in Spain for the prescription of innovative drugs including interferon beta-1b (IFNbeta-1b). Petitions for dispensing and reimbursement are based on the inclusion and exclusion criteria of pivotal trials, and are reviewed individually for approval by specialist committees. To estimate the performance of IFNbeta-1b in the clinical setting, data collected by the INSALUD and regional health services of Andalusia and Catalonia, together responsible for the healthcare of nearly 30 million individuals, were compiled in a common database for analysis. METHODS: Data comprise demographic and disease characteristics at the time of petition and at follow-up 3 months after treatment initiation and every 6 months thereafter. Efficacy was estimated by mean number of relapses per year, proportion of relapse-free patients, and disease progression as measured by the Expanded Disability Status Scale (EDSS). Safety parameters included adverse events and laboratory analyses. RESULTS: Between September 1995 and database cutoff in mid-1998, petitions of 1419 patients were approved for IFNbeta-1b treatment. Patients were homogenous across the three databases and in the subgroups of patients completing 1 year (n = 940) and 2 years (n = 302) of treatment. There was a marked decrease in the mean number of relapses in the first 12 months of IFNbeta-1b treatment for the 938 patients documented for 12 months, with a mean of 0.4 (+/- 0.7 SD) relapses per patient and year, and a 2-year mean of 0.9 (+/- 1.20 SD) in the 302 patients documented for 24 months. Of the 938 patients followed for > or = 12 months, 505 (53.8%) were documented as being relapse-free during 12 months of treatment, and 146 (48.3%) of the 302 patients followed for > or = 24 months, were relapse-free during 24 months of treatment. There were no differences in mean or median EDSS scores between baseline and months 12 and 24. Skin disorders were the most frequent adverse events, reported in over one-third of all patients; there were 159 injection site events, most frequently erythema (115 events). Systemic AEs pointing towards flu-like symptoms were reported in 288 of 1419 patients (20.3%). Leukopenia was the most frequently reported laboratory event. Elevations in liver transaminases were noted for 12 patients (0.8%) with SGOT increase and 7 (0.5%) with SGPT increase. CONCLUSION: The protocol system has helped make IFN treatment available to 8-10% of the estimated 15,000-18,000 MS patients in the regions studied. In terms of efficacy, IFNbeta-1b performed in line with the pivotal study results. The safety profile of IFNbeta-1b was consistent with the published findings and the drug labelling, and no new side effects or increased incidence of known side effects was observed.

Adjuvants, Immunologic↗