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Aspartylglycosaminuria (AGU), the most common lysosomal disorder of glycoprotein degradation, is caused by deficient activity of glycosylasparaginase (AGA). AGA-deficient mice share most of the clinical, biochemical and histopathologic characteristics of human AGU disease. In the current study, recombinant human AGA administered i.v. to adult AGU mice disappeared from the systemic circulation of the animals in two phases predominantly into non-neuronal tissues, which were rapidly cleared from storage compound aspartylglucosamine. Even a single AGA injection reduced the amount of aspartylglucosamine in the liver and spleen of AGU mice by 90% and 80%, respectively. Quantitative biochemical analyses along with histological and immunohistochemical studies demonstrated that the pathophysiologic characteristics of AGU were effectively corrected in non-neuronal tissues of AGU mice during 2 wk of AGA therapy. At the same time, AGA activity increased to 10% of that in normal brain tissue and the accumulation of aspartylglucosamine was reduced by 20% in total brain of the treated animals. Immunohistochemical studies suggested that the corrective enzyme was widely distributed within the brain tissue. These findings suggest that AGU may be correctable by enzyme therapy.-Dunder, U., Kaartinen, V., Valtonen, P., Väänänen, E., Kosma, V.-M., Heisterkamp, N., Groffen, J., Mononen, I. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria.

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BackgroundThe aims were to evaluate the effect of pregnancy on carotid artery elasticity and determine the associations between maternal lipids, endothelial function and arterial elasticity during pregnancy.MethodsWe examined 99 pregnant and 99 matched non-pregnant control women as part of a population-based prospective cohort study. Carotid artery elasticity indexes; carotid artery distensibility (CAD), Young’s elastic modulus (YEM) and stiffness index (SI) as well as brachial artery flow-mediated dilation (FMD) were assessed using ultrasound; serum lipid levels were also determined.ResultsSI was 57% and YEM 75% higher and CAD 36% lower in the third trimester group than the corresponding values in the first trimester group. Serum cholesterol and triglyceride levels were significantly higher in women at the end of the pregnancy than at the beginning of pregnancy (P < 0.001) and in controls (P < 0.001). In multivariate analysis, gestational age was the only independent correlate of arterial elasticity in pregnant women. In controls, age (P ≤ 0.001) and common carotid diameter (P = 0.001-0.029) were associated with SI, YEM and CAD.ConclusionsThe present study revealed that carotid artery elasticity declined towards the end of the pregnancy; this neither is straight correlating with maternal hyperlipidemia or the diameter of the carotid artery nor is it associated with changes in endothelial function.

The aim of the present study was to evaluate pregnancy-related changes in autonomic regulatory functions in healthy subjects. We studied cardiovascular autonomic responses to head-up tilt (HUT) in 28 pregnant women during the third trimester of pregnancy and 3 months after parturition. The maternal ECG and non-invasive beat-to-beat blood pressure were recorded in the horizontal position (left-lateral position) and during HUT in the upright position. Stroke volume was assessed from blood pressure signal by using the arterial pulse contour method. Heart rate variability (HRV) was analysed in frequency domain, and baroreflex sensitivity by the cross-spectral and the sequence methods. In the horizontal position, all frequency components of HRV were lower during pregnancy than 3 months after parturition (P < 0.01 to <0.001), while pregnancy had no influence on normalized low frequency and high frequency powers. During pregnancy haemodynamics was well balanced with only minor changes in response to postural change while haemodynamic responses to HUT were more remarkable after parturition. In pregnant women HRV and especially its very low frequency component increased in response to HUT, whereas at 3 months after parturition the direction of these changes was opposite. Parasympathetic deactivation towards term is likely to contribute to increased heart rate and cardiac output at rest, whereas restored sympathetic modulation with modest responses may contribute stable peripheral resistance and sufficient placental blood supply under stimulated conditions. It is important to understand cardiovascular autonomic nervous system and haemodynamic control in normal pregnancy before being able to judge whether they are dysregulated in complicated pregnancies.

Aspartylglycosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of glycosylasparaginase (AGA), and characterized by motor and mental retardation. Enzyme replacement therapy (ERT) in adult AGU mice with AGA removes the accumulating substance aspartylglucosamine from and reverses pathology in many somatic tissues, but has only limited efficacy in the brain tissue of the animals. In the current work, ERT of AGU mice was initiated at the age of 1 week with three different dosage schedules of recombinant glycosylasparaginase. The animals received either 3.4 U of AGA/kg every second day for 2 weeks (Group 1), 1.7 U/kg every second day for 9 days followed by an enzyme injection once a week for 4 weeks (Group 2) or 17 U/kg at the age of 7 and 9 days (Group 3). In the Group 1 and Group 3 mice, ERT reduced the amount of aspartylglucosamine by 34 and 41% in the brain tissue, respectively. No therapeutic effect was observed in the brain tissue of Group 2 mice. As in the case of adult AGU mice, the AGA therapy was much more effective in the somatic tissues than in the brain tissue of the newborn AGU mice. The combined evidence demonstrates that a high dose ERT with AGA in newborn AGU mice is up to twofold more effective in reducing the amount of the accumulated storage material from the brain tissue than ERT in adult AGU animals, indicating the importance of early detection and treatment of the disease.

Improvement of FMD in normal pregnancy was not affected by increase in hsCRP concentration. We found an association with IL-6 and FMD but we believe that improvement in endothelial function during normal pregnancy is not caused by variation in hsCRP, IL-6 or TNF-alpha.

BackgroundThe aim was to evaluate the metabolic profile in conjunction with vascular function using the ambulatory arterial stiffness index (AASI) in women with uncomplicated pregnancies and in women with gestational diabetes mellitus (GDM).MethodsPlasma glucose, lipids, HOMA –IR (homeostasis model assessment of insulin resistance) and AASI, as obtained from 24-hour ambulatory blood pressure monitoring in third trimester pregnancy and at three months postpartum, were measured in three groups of women: controls (N = 32), women with GDM on diet (N = 42) and women with GDM requiring insulin treatment (N = 10).ResultsWomen with GDM had poorer glycemic control and higher HOMA-IR during and after pregnancy and their total and LDL (low density lipoprotein) cholesterol levels were significantly higher after pregnancy than in the controls. After delivery, there was an improvement in AASI from 0.26 ± 0.10 to 0.17 ± 0.09 (P = 0.002) in women with GDM on diet, but not in women with GDM receiving insulin whose AASI tended to worsen after delivery from 0.30 ± 0.23 to 0.33 ± 0.09 (NS), then being significantly higher than in the other groups (P = 0.001-0.047).ConclusionsWomen with GDM had more unfavorable lipid profile and higher blood glucose values at three months after delivery, the metabolic profile being worst in women requiring insulin. Interestingly, the metabolic disturbances at three months postpartum were accompanied by a tendency towards arterial stiffness to increase in women requiring insulin.