Twenty-four-month alpha-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipids in different tissues including endothelial cells and smooth-muscle cells and cardiomyocytes, and cardiovascular complications are common in the disease. Since 2001, specific enzyme replacement therapy (ERT) with alpha-galactosidase A has been available. It has been reported to improve clinical symptoms and quality of life. However, limited and controversial data on its efficacy to cardiac involvement have been published. Nine patients (5 male) with Fabry disease were included in an open-label prospective follow-up study of 24-month ERT. Comprehensive cardiovascular evaluation was performed by MRI, stress echocardiography and quality of life assessment. Plasma globotriaosylceramide decreased from 6.2 to 1.4 microg/ml during ERT (p<0.05). The only other measured parameters that changed significantly were resting heart rate that decreased from 79 to 67 bpm (p<0.01) and end-systolic volume that decreased by 12.4 ml (p<0.05). The other parameters consisting of quality of life, self-estimated cardiovascular condition, diastolic function, exercise capacity, ECG parameters, ejection fraction and ventricular mass did not change. ERT has only minimal effect on symptoms and cardiovascular morphology and function in Fabry disease. Therefore, effective conventional medical therapy is still of major importance in Fabry disease. Larger ERT studies are warranted, especially in women, to solve current open questions, such as the age at which ERT should be started, optimal dosage and intervals between infusions. Furthermore, longer follow-up studies are needed to assess the effects of ERT on prognosis.

The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease.

Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient alpha-galactosidase A activity which leads to the widespread accumulation of globotriaosylceramide (Gb(3)) and related glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. We have recently shown that the myocardial perfusion reserve of Fabry patients is significantly decreased. Thus, in the present study we investigated, whether it can be improved with enzyme replacement therapy (ERT). Ten patients (7 male, 3 female; mean age 34, range 19-49 years) with confirmed Fabry disease were approved for this uncontrolled, open-label study. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and radiowater. Myocardial perfusion reserve was calculated as the ratio between maximal and resting perfusion. Perfusion measurements were performed before and after 6 and 12 months of ERT by recombinant human alpha-galactosidase A (Fabrazyme, Genzyme). Plasma Gb(3) concentration decreased significantly and the patients reported that they felt better and suffered less pain after the ERT. However, neither resting or dipyridamole-stimulated myocardial perfusion nor myocardial perfusion reserve changed during the ERT. Pretreatment relative wall thickness correlated negatively with posttreatment changes in flow reserve (r = -0.76, p = 0.05) and positively with posttreatment changes in minimal coronary resistance (r = 0.80, p = 0.03). This study shows that 12 months of ERT does not improve myocardial perfusion reserve, although the plasma Gb(3) concentration decreases. However, individual variation in the response to therapy was large and the results suggest that the success of the therapy may depend on the degree of cardiac hypertrophy.

Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease.

Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient alpha-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly known. We studied 15 Fabry patients (mean age 35 years and mean BMI 24.8 kg/m2) and 30 age- and BMI-matched healthy controls to examine whether myocardial perfusion reserve and peripheral artery endothelial function are altered. Myocardial perfusion was measured at rest and during dipyridamole-induced hyperaemia by positron emission tomography and H2(15)O. Myocardial blood flow reserve was calculated as the ratio between the dipyridamole-induced maximal blood flow and resting blood flow. Peripheral artery endothelial function was assessed by measuring the brachial artery flow-mediated dilatation using ultrasound at rest and during reactive hyperaemia. The myocardial perfusion reserve was significantly lower in Fabry patients than in controls (3.3+/-1.2 vs 4.4+/-1.6, p=0.02), while the brachial artery flow-mediated dilatation was similar (5.9%+/-3.9% vs 4.5%+/-3.6%, p=0.27). Thus, inFabry disease, myocardial perfusion reserve is reduced while the peripheral artery endothelial function is preserved.

Controlled lengthening or shortening contraction-induced damage is followed by fiber hypertrophy in rat skeletal muscle.

To study the hypothesis that more severe damage, caused by controlled lengthening (L) contractions, results in greater myofiber hypertrophy compared to increase in fiber size followed shortening (S) contractions, tibialis anterior muscles of anesthesized male Wistar rats were subjected to 240 either L or S contractions. The highest increase in muscle beta-glucuronidase activity, an indicator of muscle damage, was observed in L (7.1-fold) 4 days and in S (2.6-fold) 8 days postexercise. Dystrophin- and desmin-negative as well as fibronectin-positive fibers (signs of the early phase of damage) were observed immediately after exercise in the L group. At 4 days, massive myofiber injury was visible, and internally localized nuclei were present at 15-80 days after exercise in the L group. The shift towards more glycolytic fiber types (p<0.05 in L and S) and an increased mean cross-sectional area of type IIX/B fibers (p < 0.001 in L and S) at 80 days were observed in both groups. The observed minor damage with unchanged myofiber structures following S induced, however, an increase in myofiber cross-sectional area of nearly the same magnitude as that following L, which was more damaging. The results do not support the hypothesis that fiber hypertrophy depends on the extent of the myofiber damage upon the exercised muscles.

Gender differences in skeletal muscle fibre damage after eccentrically biased downhill running in rats.

Specific antibodies against structural proteins of muscle fibres (actin, desmin, dystrophin) and extracellular matrix (fibronectin) were used to study the effect of eccentrically biased downhill running exercise (13,5 degrees, 17 m min(-1), 130 min) on the magnitude and properties of myofibre injury in the quadriceps femoris muscle of male and female rats. Muscle beta-glucuronidase activity, a quantitative indicator of muscle damage, showed clearly smaller increase in female than in male rats during the 4-day period following exercise. A similar course of histopathological changes was observed in both sexes, although females showed slower and less marked changes than males. In males, discontinuous or even lost submembrane protein dystrophin staining was observed in some swollen fibres immediately after exercise, before the loss of desmin and staining of disorganized actin, i.e. before the disruption of the cytoskeletal system and the contractile apparatus. The observation that no dramatic changes in the microarchitecture of the muscle fibres were detected immediately or even 6 h after the exercise in females compared with males may indicate that the sarcolemma of the females might be strengthened against membrane damage by a still unknown stabilizing compound.

Epidemiology of invasive pneumococcal infections in children in Finland.

OBJECTIVE: To study the epidemiologic characteristics of invasive infections in children caused by Streptococcus pneumoniae to provide background data for vaccination programs. DESIGN: A nationwide laboratory-based prospective surveillance of all invasive pneumococcal infections in children during 1985 through 1989. SETTING: A network of all microbiologic laboratories and pediatric wards in Finland. PATIENTS: Children aged 0 to 15 years who were admitted to a hospital with S pneumoniae isolated from blood, cerebrospinal fluid, or deep aspirate sample. RESULTS: Four hundred fifty-two invasive pneumococcal infections were diagnosed in 1985 through 1989. The annual incidence rate was 8.9 per 100,000 children less than 16 years of age (24.2 per 100,000 among children less than 5 years of age and 45.3 per 100,000 among those less than 2 years of age). The most common clinical entities were bacteremia without focus (310 cases), pneumonia (66 cases), and meningitis (51 cases), with other focal infections seen in 25 cases. The pneumococcal groups/types 14, 6, 19, 7, 18, and 23 comprised 78% of all invasive infections. CONCLUSIONS: Streptococcus pneumoniae is a common cause of invasive infections in children in Finland. A pneumococcal conjugate vaccine containing the six most common groups/types could prevent up to 70% of invasive pneumococcal infections of children in Finland if fully protective in infancy.

Pneumococcal finding in a sample from upper airways does not indicate pneumococcal infection of lower airways.

The presence of pneumococcus (Pnc) by antigen detection and culture was examined in nasopharyngeal aspirates (NPA) of 315 children hospitalized with middle or lower respiratory tract infection. Pnc was found in NPA from 115 (37%) patients, being demonstrated by antigen detection alone in 34 (30%), by culture alone in 26 (23%) and by both methods in 55 (48%) of Pnc-positive samples. Pnc findings in NPA were most common, 45-46%, in patients aged 1-4 years. Serological evidence of Pnc infection, based either on detection of Pnc antigen in serum or urine, or on demonstration of an antibody response to these antigens, was present in 31 (27%) of the 115 patients with and in 28 (14%) of the 200 patients without Pnc in NPA samples. In the 48 patients positive for Pnc in NPA samples both by antigen detection and culture the isolated Pnc strains were serotyped. In 45 (94%) of these the type/group of Pnc was the same by both methods indicating that the specificity of the antigen detection tests, latex particle agglutination and counterimmunoelectrophoresis, was high. To evaluate the diagnostic significance of Pnc antigen detection and culture in NPA, sensitivity, specificity and likelihood ratios were calculated; serological evidence of Pnc aetiology was used as a reference. For both methods, sensitivity was poor, less than 0.3, but specificity was good, greater than 0.8. It is concluded that the finding of Pnc by culture or antigen detection in NPA is no indication of Pnc respiratory infection. On the other hand, Pnc etiology is unprobable, if Pnc is not present in NPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Variability of penicillin-binding proteins from penicillin-sensitive Streptococcus pneumoniae.

Penicillin-binding proteins (PBPs) from penicillin-susceptible strains of Streptococcus pneumoniae are believed to be fairly similar in contrast to PBPs occurring in resistant isolates. The antigenic variation of PBPs 1a and 2b in 65 penicillin-susceptible strains from different geographic areas and a wide variety of isolation sites was analyzed using a set of specific antisera and monoclonal antibodies. Three strains contained different antigenic variants of PBP 1a, and 50 strains contained one of three antigenic variants found in PBP 2b. Seven patterns of antibody reactivity could be defined; all but one were distinct from those found recently in resistant strains. In addition, electrophoretic mobilities of all six PBPs, compared after conventional SDS-PAGE and fluorography, revealed an unexpected variation of PBP-profiles even for strains of one sero-group. Few strains appeared identical to each other or to the laboratory reference strain R6.

Antigenic variation of penicillin-binding proteins from penicillin-resistant clinical strains of Streptococcus pneumoniae.

Penicillin-resistant strains of Streptococcus pneumoniae that are isolated with increasing frequency worldwide contain low-affinity penicillin-binding proteins (PBPs). The relatedness of PBPs from 55 resistant strains isolated on three continents was investigated by testing the reactivity of antibodies specific for PBP 1a or 2b and by comparing the PBP patterns. Seventeen patterns of antibody reactivity could be distinguished, 12 of which were specific to one isolate. Most strains, including all German and South African strains, had a unique PBP profile. A few groups of Spanish and Finnish isolates were identified where the strains within each group shared the same PBP profile, the same antigenic variants of PBPs 1a and 2b, and the same serogroup, suggesting that they represent different clones of S. pneumoniae. The results demonstrated highly variable pathways of resistance development and confirmed that resistant strains have emerged independently in different locations.

Antibody response to 14-valent pneumococcal capsular polysaccharide vaccine in pre-school age children.

Antibody responses to 14-valent pneumococcal capsular polysaccharide vaccine were measured by Farr-type radioimmunoassay in children younger than 7 years of age. On the basis of immunogenicity in young children individual pneumococcal polysaccharides could be identified as uniformly good, strongly age-dependent or uniformly poor immunogens. Pneumococcal types 6A and 23F, which frequently cause pneumococcal infections in small children, were the poorest immunogens in this age group. The children younger than 2 years of age responded very poorly also to types 19F and 18C whereas older children had good antibody responses to these types. The results support the current view that present pneumococcal polysaccharide vaccines are not beneficial in children younger than 2 years of age and stress the importance of attempts to improve their immunogenicity.