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Biomedical subjects

J A Aznar

Publications and source records attributed to J A Aznar.

At least 19 recordsLinked to original sources

Effects of dynamic rotation on event-related brain potentials.

Event-related potentials were recorded during a mental rotation task. Subjects were shown pairs of letter-like shapes and were asked to make a parity judgment. The shape on the left was always in its canonical position and the shape on the right could either be in its canonical position or be a mirror image. Two variables were manipulated for the shape on the right. First, it could appear at different orientations (50 degrees , 100 degrees or 150 degrees ); second, it could be presented in a stationary position, in a dynamic congruent direction (the shape slowly rotating toward its normal upright position) or in a dynamic incongruent direction (the shape slowly rotating in the opposite direction to its normal upright position). Orientation- and direction-dependent modulations of a negative slow wave were found. For orientation, the typical amplitude effect over parietal sites was found, the amplitude becoming more negative as the rotational angle increased. For direction, the amplitude of the negative slow wave was larger for stationary and dynamic incongruent trials than for dynamic congruent trials at 100 degrees and 150 degrees . This result suggests that presentation of a stimulus in a dynamic congruent direction facilitates the mental rotation process. At 50 degrees , differences between dynamic incongruent trials and both stationary and dynamic congruent trials were found, suggesting that the incongruent movement elicits an obstructing effect over the mental rotation process. In summary, the present experiment provides new evidence in support of the idea that the amplitude modulation over the parietal cortex is a psychophysiological marker of the mental rotation process.

Adolescent↗

Results of an orthopaedic survey in young patients with severe haemophilia in Spain.

This paper outlines the results obtained in a cross-sectional study of a group of young patients with severe haemophilia A and B. The primary aim of the study was to ascertain the level of orthopaedic complications in the group, the effects that these complications have on quality of life, and the medical resources used on these patients. The secondary aim was to relate their current orthopaedic state to the type of treatment received before the study. The study was carried out in 11 hospitals in Spain, where 70 severe haemophilia patients (factor VIII [FVIII] < 2%), with an average age of 21.6 and a median age of 22, and no inhibitors, were monitored. The percentage of patients suffering from articular complaints was 84.3% and 85.7% according to the Gilbert and Petterson scales, respectively. Furthermore, pain was reported in 16.1% of joints, most frequently in ankles. Using the SF-36 Health Survey, patients were observed to have a poorer quality of life relative to healthy controls. Despite high levels of both the coagulant factor given to patients and the financial resources dedicated to their treatment, the type of treatment (on demand and/or as secondary prophylaxis) provided to the young adults was found to be incapable of preventing haemophilic arthropathy and subsequent negative quality of life consequences.

Absenteeism↗

Orthoses in haemophilia.

In haemophilia patients, orthoses are used for the prevention and management of bleeds and their effects on the musculoskeletal system. The characteristics of these devices vary according to the joint to which they are applied, although two basic types are distinguished: static and functional. The upper limbs make up a functional unit that is adapted to prehension, or the action of grasping or seizing objects. The most affected joints of this unit in haemophilia are the elbow and shoulder, which require immobilization, followed by stabilization and protection and in the case of disability, assistance in the performance of function. The lower limbs, on the other hand, are adapted to the action of ambulation. The knee, ankle and hip joints frequently sustain damage in haemophilia, and in the acute phase they should be immobilized and the patient discouraged from walking. Once bleeding has ceased, and motion and muscle balance improved, a gradual return to normal activity may commence. The principle aim of orthotics in these cases is to immobilize and unburden the affected body segment, and to provide stability and assistance for ambulation. Shoe insoles cushion and modify stance, and therefore may help prevent lesions. Crutches and walking frames are used for restoring normal gait. Orthotic devices improve the quality of life of haemophilia patients with musculoskeletal lesions and are useful for preventing lesions resulting from strenuous activities, whether performed in the course of daily living or in the pursuit of games and sports.

Hemarthrosis↗

Association of the 3467C>T mutation (T1156M) in the von Willebrand's factor gene with dominant type 1 von Willebrand's disease.

Type 1 is the most frequent form of von Willebrand's disease, which is characterized by a quantitative partial deficiency of von Willebrand's factor. At present, only two mutations located in the D3 domain (C1149R, C1130F) have been reported to cause the classic type 1 variant. The 3467C>T transition that predicts the T1156M amino acid change was detected in seven patients from one family and was not found in 110 normal alleles screened. This is a candidate mutation to cause dominant type 1 variant with complete penetrance. On the other hand, neither of the two mutations mentioned above has been detected in the other 15 families studied with type 1 or possible type 1 patients.

Alleles↗

Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age.

The potential effect of age at the start of replacement therapy on the development of factor VIII (FVIII) inhibitors was assessed in 62 severe (FVIII < 2 IU/dl) haemophilia A patients who started FVIII therapy at one of two haemophilia centres. Inhibitors were tested on an annual basis. Persistent or high-titre inhibitors were detected in 15 patients (24%). Kaplan-Meier cumulative incidence at 3 years from first FVIII exposure was 41% (95% CI 22-67%) in patients starting therapy before the age of 6 months, 29% (95% CI 13-57%) in patients starting therapy between 6 and 12 months of age, and 12% (95% CI 4-34%) in those starting therapy beyond 1 year of age (P = 0.03). By multivariate analysis, the influence of age was shown to be independent of other variables, including calendar year at the onset of therapy and baseline FVIII plasma levels. In conclusion, patient age at initial treatment appears to influence inhibitor formation. If confirmed, this finding would have a major impact on the management of haemophilia.

Age Factors↗

Significant linkage and non-linkage of type 1 von Willebrand disease to the von Willebrand factor gene.

Significant linkage of types 2A and 2B von Willebrand disease (VWD) to the von Willebrand factor (VWF) gene have been reported, as well as mutations in the VWF gene. However, data for the partial quantitative variant are less consistent. An inconsistency of association between the type 1 VWD phenotype and genotype has been reported recently. We undertook linkage analysis of 12 families with definite or possible type 1 VWD patients. One family with classic type 1 VWD had a high lod score (Z = 5.28, theta = 0.00). A total lod score of 10.68 was obtained for the four families with fully penetrant disease. In two families linkage was rejected, while three families did not show conclusive evidence of linkage. This study corroborates ABO blood group influence, especially in patients with mild deficiencies and/or incomplete penetrance. Indirect genetic analysis may be an option for diagnosing asymptomatic or presymptomatic type 1 VWD carriers, particularly in families showing higher penetrance. The study indicates defects of the VWF locus are to be expected in more than half of the families studied. However, as defects at different loci may be the cause of this phenotype, the results of the segregation analyses should be interpreted with caution, especially in studies involving small families, or mild expressions of the disorder or incomplete penetrance.

ABO Blood-Group System↗

Post-synoviorthesis rehabilitation in haemophilia.

The efficacy of radiosynoviorthesis in the management of chronic haemophilic synovitis has been proven. Like replacement therapy, however, this procedure has no effect on muscle strength or endurance, range of movement, coordination, or the patient's physical condition in general. All the factors just enumerated are essential for the recovery and maintenance of the haemophiliac's quality of life. That is why rehabilitation and physiotherapy are so important, since no medical therapy or surgical procedure are by themselves capable of preventing disabilities.

Hemarthrosis↗

Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry.

We present a retrospective study of immune tolerance treatment (ITT) carried out in 42 Spanish haemophiliac patients. Most of the patients were high responders (39/42), with a median maximum titre of 67 Bethesda units (BU) (range 6-2984). The median inhibitor titre at the start the ITT was 11 BU (range 1-256 BU) and the median age of the patients was 7 years (range 0-57). The mean factor dosage was 140 IU kg bodyweight(-1) day(-1) (range 25-500). In most of the ITTs, plasma-derived factor concentrate of intermediate and high purity was used. The inhibitor was eradicated in 26/38 (68%) of the patients who completed the treatment and two patients changed their status from high to low responders. Multivariate logistic regression analysis showed that three significant variables were associated with the highest probability of success: (i) the use of low factor doses for ITT (< or = 100 IU kg(-1) day(-1); P = 0.0106; 95% CI 0.000289-0.342); (ii) a titre of < 10 BU at start of ITT (P = 0.0286; 95% CI 0.00253-0.7189) and (iii) a lower maximum titre (P = 0.0214; 95% CI 0.98-0.9994).

Actuarial Analysis↗

A comparison of FVII:C and FVIIa assays for the monitoring of recombinant factor VIIa treatment.

The use of recombinant factor VIIa (rFVIIa) is on the increase, not only to treat haemophilic patients with inhibitors, but also patients with other clotting disorders. However, the most appropriate method of monitoring this treatment remains a question that has yet to be resolved. We studied 24 plasma samples from patients receiving rFVIIa treatment (three had haemophilia A with inhibitors, and three a congenital FVII deficiency) and compared the results obtained from the FVII:C and FVIIa assays. Although a good correlation between the two methods was obtained (r = 0.91), the values of the FVII:C method were 1.63 higher than those of the FVIIa method, with a relatively wide margin in the interval of the FVII:C/FVIIa ratios obtained [95% confidence interval (CI) 1.38--1.88, range 0.68--3.68]. This interval became wider when we compared values of over 6 IU mL(-1), which led us to conclude that the two methods cannot be considered equivalent. As the FVIIa method specifically measures FVIIa, and FVII:C assay is known to have a wide interlaboratory variability, we believe that the FVIIa assay would be more suitable for the monitoring of rFVIIa treatment.

Antigens↗

Influence of von Willebrand factor on the reactivity of human factor VIII inhibitors with factor VIII.

In order to determine the difference in reactivity of factor (F) VIII inhibitors against the FVIII/von Willebrand factor (vWF) complex and against vWF-deficient FVIII, we investigated a panel of 10 antibodies to FVIII from multitransfused individuals with severe haemophilia A and other pathologies. Immunoblotting of purified FVIII and purified thrombin-cleaved FVIII revealed that in all cases inhibitor epitopes could be localized in the heavy chain (A2 subunit) while in four cases they were also present in the light chain. One of the FVIII inhibitors remained unclassified. The effect on FVIII:C of purified IgG from inhibitor plasmas was tested against a high purity FVIII/vWF concentrate and a monoclonally purified FVIII concentrate with only trace contents of vWF, by two different functional assays. Our results suggest that for those inhibitors showing A2 plus light chain (LC) reactivity, the IgG concentration required to inhibit 50% of FVIII activity in vitro is higher for the FVIII/vWF complex than for the vWF-deficient FVIII. We conclude that there might be a protective role of vWF (at least in vitro) against FVIII inhibitors with A2 and LC subunit specificity.

Antibodies↗

New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand's disease.

BACKGROUND AND OBJECTIVES: von Willebrand's disease (vWD), the most common hereditary bleeding disorder in humans, is caused by qualitative and/or quantitative deficiencies of von Willebrand factor, and can manifest itself under several different phenotypes. Most of the molecular defects have been detected in qualitative variants involving exon 28 of the vWF gene. Patients from four unrelated families with different types of vWD were included in the mutation screening of this region. DESIGN AND METHODS: The whole exon 28 was analyzed in three gene specific fragments, two of them comprising the region involved in the platelet glycoprotein Ib vWF interaction. The search for mutations was carried out by single-stranded conformation polymorphism analysis. The mutations were then identified by automatic sequencing of the anomalous electrophoretic pattern samples. RESULTS: The following candidate mutations were detected. The 3941T-->A transversion, which predicts the amino acid change V1314D, was detected in a sporadic patient with type 2B vWD and severe thrombocytopenia. The 4309G-->A transition, resulting in the amino acid substitution A1437T, was identified in four patients classified as having type 2M vWD. Six unclassified patients from another family carry the 4135C-->T mutation, which gives rise to a cysteine instead of the normal arginine (R1379C) that segregates with the phenotype. The amino acid change C1227R, predicted by the mutation 4135C-->T, was identified as a compound heterozygote in a patient with moderately severe type 1 vWD. None of these mutations had been described previously. INTERPRETATION AND CONCLUSIONS: These findings confirm the importance already given to this region for the correct function of von Willebrand factor since the mutations detected, which affect the D3 and A1 domains, could give rise to different variants of the disease.

Child↗

Progression to acquired immunodeficiency syndrome in 94 human immunodeficiency virus-positive hemophiliacs with long-term follow-up.

BACKGROUND AND OBJECTIVES: Human immunodeficiency virus (HIV) infection was transmitted to many hemophilics treated with non-inactivated factor concentrates before 1986. The aim of this study was to know the long-term incidence of AIDS and risk factors for its development in HIV-infected hemophiliacs. DESIGN AND METHODS: This study was a retrospective analysis of 94 HIV-infected hemophilics. The cumulative incidence of AIDS during a follow-up of 16 years from seroconversion was determined by Kaplan-Meier analysis,and potential risk factors were also studied by multivariate analysis. RESULTS: The 16-year estimated incidence of AIDS was 38% (95%CI 27%-52%). The AIDS incidence was significantly higher in patients with hemophilia B (p <0.0001), older age at seroconversion (p=0.0004), lower CD4 counts at seroconversion (p=0.004), and lower concentrate consumption during follow-up (p=0.02), than it was in those patients without these characteristics. However, only hemophilia type and age at seroconversion remained significant in the multivariate analysis, with a relative risk of 0.06 (95%CI 0.02-0.20) for hemophilia A and 1.04(95%CI 1.01-1.06) for every year of increase in age at seroconversion. The severity of hemophilia, history of inhibitors and concentrate consumption before seroconversion were not significantly associated with AIDS development. INTERPRETATION AND CONCLUSIONS: A considerable proportion of HIV-infected hemophiliacs remained AIDS-free 16 years after seroconversion. The risk of AIDS was particularly high in patients with hemophilia B and for patients who were older at seroconversion.

Acquired Immunodeficiency Syndrome↗

Evaluation of an automated method for the quantification of von Willebrand factor antigen. Its application in the study of vascular dysfunction.

BACKGROUND AND OBJECTIVES: Abnormally high levels of von Willebrand factor (VWF) have been described as a response to physiologic and chronic alterations. It is therefore of great interest to have sensitive, accurate, fast and easy to use assays to quantify VWF. The aim of this study was to evaluate the performance characteristics of the immunoturbidimetric assay IL Test VWF:Ag and the use of this determination in the study of vascular dysfunction. DESIGN AND METHODS: The reproducibility, accuracy and linearity of the method were determined. A method comparison study was performed using an ELISA as the reference test. The assay reference range and its age-dependence were established. To evaluate the utility of the assay in vascular dysfunction, a cohort of 30 type 1 diabetes mellitus (DM) patients were analyzed, 11 of whom showed microvascular complications. RESULTS: The linearity range found was 10-150 IU/dL. Reported values above 150 IU/dL should be diluted and reanalyzed, expanding the range up to 600 IU/dL. The coefficients of variation were below 5% and inaccuracies below +/-15% within the linearity range. The comparison with the reference ELISA showed a good correlation coefficient (r = 0.985, VWF values from 5-680 IU/dl). The reference range was found to be 40.8 - 158.1 IU/dL. Significant differences between the DM type 1 patients with microvascular complications and a sex-age matched control group were observed. This difference was not observed for the DM patients not showing vascular alterations. INTERPRETATION AND CONCLUSIONS: The method is reproducible, accurate and linear. The assay correlates well with the reference ELISA. There is a relationship between patients showing microvascular diabetic complications and high levels of VWF:Ag. The assay is easy to perform, fully automated, and suitable for analyzing a small number of samples.

Adolescent↗

Q1311X: a novel nonsense mutation of putative ancient origin in the von Willebrand factor gene.

Type 3 von Willebrand disease, a recessive autosomally inherited bleeding disorder, refers to complete deficiency of von Willebrand factor (VWF). The novel Q1311X mutation was detected in the homozygous state in four Spanish patients from two apparently unrelated families of gypsy origin. The lack of specific amplification of platelet VWF cDNA from two of the patients indicates reduced levels of mutated gene expression. The similar haplotype linked to mutated alleles suggests a common origin. On the basis of the two instabilities observed and the estimated mutation rate of the microsatellites of intron 40 of the VWF gene, we can estimate that this mutation could have arisen about 2300 years ago.

Codon, Nonsense↗

Diagnosis of two related carriers of severe haemophilia B with no family history.

Haemophilia B is an X-linked disease affecting 1 in 30 000 males. Carrier diagnosis is usually carried out only in female relatives of haemophilic males, and the likelihood of discovering a carrier without a haemophilic male is very low. In this report we present the cases of two related women without a family history of haemophilia who were diagnosed as haemophilia B carriers. Following a minor haemorrhage in the proband, she and her mother were thought to be haemophilia B carriers because of a low factor IX level (16 and 23 IU dL-1, respectively; normal values >50 IU dL-1). The non-sense mutation C31118T, which is associated with severe haemophilia B, was detected in both women. This allowed us to diagnose them as being definite carriers of severe haemophilia B and give appropriate genetic counselling.

Adult↗

The orthopaedic status of severe haemophiliacs in Spain.

This paper provides an outline of the results obtained in a cross-sectional study conducted primarily with the aim of ascertaining orthopaedic complications in a group of young severe A and B haemophiliacs, the effects which these complications have on the medical resources used with these patients, and the impact of severe haemophilia on their quality of life. Its secondary aim was to link their current orthopaedic status to the type of treatment they had received prior to the study. Eleven Spanish hospitals took part in this study, monitoring 70 severe haemophiliacs (FVIII:C <2%) without inhibitors who had a mean age of 21.6 years and a median age of 22. Retrospective data collected from birth to the conclusion of the study were used and, for certain variables, data from the last 12 months. The type of treatment given had been on-demand treatment, together with prophylaxis of variable time periods, which in 32 cases (45.7%) were prolonged (>6 months). In 40 cases (57.1%) the patients underwent one or more periods of prophylaxis. Thirty-three patients (47.8%) had over 1000 days of administration of factors VIII and IX. The analysis of the total study group reveal an average of 348 bleeding episodes per patient. The findings of this study revealed that 84.3% of these patients suffer from articular complaints on the Gilbert scale, and 85.7% on the Pettersson scale. In addition, pain was reported in 16.1% of the joints, the most frequently affected being the ankle joints. Twenty-six patients (37%) had undergone orthopaedic surgery from the time of birth to the conclusion of the study. The quality of life of the severe haemophiliacs reviewed seems to have been affected. During the last 12 months, there were 216 outpatient haematological visits and 176 orthopaedic-rehabilitation visits, as well as 12 radiological explorations and two hospitalizations. During these 12 months, medical expenditure totalled $55 473 per patient per year, the most important item being factor concentrates VIII/IX ($54 119 per patient per year). The type of treatment given to these patients (on-demand and/or as secondary prophylaxis) was found to be incapable of preventing haemophilic arthropathy or guaranteeing an acceptable quality of life, although both the administration of coagulant factor concentrate to such patients and the financial resources dedicated to their treatment was very high. Consequently, a strategic change is to be considered for the prevention of haemophilic arthropathy, based on the introduction of replacement treatment involving continuous administration of factors VIII and IX in primary prophylaxis regimens from the first years of life.

Adolescent↗