Posterior fontanelle sonography: an acoustic window into the neonatal brain

BACKGROUND AND PURPOSE: Sonographic brain studies are classically performed through the anterior fontanelle, but visualization of posterior supratentorial and infratentorial structures is poor with this approach. Posterior fontanelle sonography is recommended for better assessment of these structures. Our purpose was 1) to determine whether sonography of the brain through the posterior fontanelle (PF) improves visualization of brain lesions when added to the routine anterior fontanelle (AF) approach and 2) to describe standardized PF coronal and sagittal sections. METHODS: In this prospective study (conducted from February 1999 to January 2001), PF sonography was added to AF sonography in 165 consecutive premature neonates with a birth weight of < 2000 g. Sonograms were recorded in digital format for re-evaluation at the end of the study. Lesions were grouped as congenital, infectious, hemorrhagic, or hypoxic-ischemic. The chi2 test for paired data and the kappa coefficient were used to compare diagnoses with AF alone and diagnoses with AF plus PF. RESULTS: PF sonography was performed in 164 of 165 patients. Results were normal in 86 and abnormal in 78. The single posterior fossa malformation detected in this series was best delineated with the PF approach. PF sonography increased the diagnostic rate of grade II hemorrhage by 32%. Cerebellar hemorrhage (two patients) and cerebellar abscesses (one patient) were diagnosed by using the PF approach. PF sonography did not contribute to the diagnosis of periventricular leukomalacia. CONCLUSION: Study of the neonatal brain with the addition of PF sonography afforded greater accuracy in detecting intraventricular hemorrhage compared with AF sonography alone, especially when the ventricle was not dilated. The PF approach better defines posterior fossa malformations.     

Protein-losing hypertrophic gastropathy: another cause of gastric wall thickening in children

Protein-losing hypertrophic gastropathy (PLHG) is an uncommon, self-limited disease in young children that can produce generalized edema, hypoproteinemia, and nonspecific prodromic symptoms. Recently, Helicobacter pylori and cytomegalovirus infections have been reported to be associated with this condition. We present the case of an 18-month-old boy with PLHG and positive detection of H. pylori on fecal culture. Abdominal sonography demonstrated gastric wall thickening with preservation of the mucosal layers. Sonographic findings are useful for suggesting a diagnosis of PLHG and is also an effective, noninvasive technique for follow-up of children with this condition.     

Myotonic dystrophy associated with variable circadian rhythms of serum cortisol and isolated thyrotropin deficiency

We describe a case of myotonic dystrophy presenting with a disturbed circadian rhythm of the serum cortisol and an isolated thyrotropin deficiency. The diagnosis of myotonic dystrophy was based on clinical characteristics, positive electromyographic findings, and increased number of CTG repeats in the dystrophia myotonica protein kinase (DMPK) gene. The patient presented with a variable circadian rhythm of the serum cortisol, increased excretion of urinary free cortisol, and a high adrenocorticotropin hormone responses to corticotropin-releasing hormone. The basal serum thyrotropin concentration was low and did not increase after thyrotropin-releasing hormone stimulation. The protein encoded by the DMPK gene may act as a second messenger in signal transduction, like a protein kinase. The present patient had a diverse pattern of disturbances in the hypothalamus-pituitary-endocrine organ axis, probably mediated by differences in the action or expression of the gene products in each endocrine cell.     

Vitamin E-bonded hemodialyzer improves atherosclerosis associated with a rheological improvement of circulating red blood cells

BACKGROUND: Vitamin E-bonded hemodialyzer is known to improve oxidative stress in patients with hemodialysis. However, there is little information available as to whether or not this membrane clinically improves atherosclerosis. Furthermore, it remains unknown whether there is any effect of the membrane on rheology of circulating red blood cells. METHOD: We conducted a randomized, open-labeled, prospective control study (N = 34) for 1 year to investigate the effect of vitamin E-bonded cellulose membrane dialyzer (EE) (N = 17) on carotid atherosclerotic changes [intima-media thickness (IMT) of carotid arteries] and the viscosity, percentage of dysmorphism (%DMR) of red blood cells (RBCs) and their distribution width-standard deviation (RDW-SD), in comparison with cellulose membrane (SU) (N = 17) identical to EE without vitamin E-bonded membrane. Erythropoietin (EPO) dose used for the treatment of uremic anemia was also calculated. RESULTS: The IMT significantly decreased in the EE group, while in the SU group the IMT significantly increased. The viscosity of RBCs in hemodialysis patients (4.70 +/- 0.45 cP) was greater than that in healthy individuals (3.73 +/- 0.15 cP). EE significantly improved the viscosity (from 4.84 +/- 0.41 cP to 4.51 +/- 0.54 cP, P < 0.01), %DMR (from 2.29 +/- 2.17% to 1.90 +/- 1.49%, P < 0.01), and RDW-SD (from 54.4 +/- 7.6 fL to 49.3 +/- 5.9 fL, P < 0.01). On the contrary, these parameters all worsened in the SU group. EPO dose needed for the treatment of anemia was significantly (P < 0.05) reduced from 5383 +/- 2655 U/week to 4235 +/- 3103 U/week in the EE group. During these period, mean blood pressure, Kt/V urea, and serum beta2-microglobulin were not changed between the two groups. CONCLUSION: These findings suggest that vitamin E-bonded hemodialyzer is very useful for improving atherosclerosis from a clinical point of view. As one of the underlying mechanisms, as well as antioxidant effects, we want to address an important role of the improvement of rheology of circulating RBCs, which may also help to reduce the requirement of EPO dose in the treatment of anemia of ESRD patients.     

Inactivation and Aggregation of β-Galactosidase in Lyophilized Formulation Described by Kohlrausch-Williams-Watts Stretched Exponential Function

Purpose. To examine whether the empirical Kohlrausch-Williams-Watts (KWW) equation is applicable not only to protein aggregation but also to protein denaturation in lyophilized formulations. Lyophilized -galactosidase (-GA) formulations containing polyvinylalcohol and methylcellulose were used as model formulations. The possibility of predicting storage stability based on the temperature dependence of the estimated parameters of inactivation/aggregation—time constant () and its distribution () is discussed. Methods. Protein aggregation in lyophilized -GA formulations at 10-70°C and 6-43% relative humidity was determined as a function of time by size exclusion chromatography. Enzyme activity was also determined using 2-nitrophenyl--D-galactopyranoside as a substrate. Results. Inactivation and aggregation of -GA were describable with the empirical KWW equation, regardless of whether the temperature was above or below the NMR relaxation-based critical mobility temperature (T_mc) or whether protein molecules with different degrees of deformation resulting from stresses during lyophilization exist in the formulation. The estimated parameter for protein aggregation decreased rapidly as temperature increased beyond T_mc because the mobility of polymer molecules increased in the initial stages of glass transition. The time required for 10% enzyme to aggregate (t₉₀) calculated from the and parameters exhibited a change in temperature dependence gradient near T_mc. In contrast, t₉₀ for protein inactivation exhibited temperature dependence patterns varying with the excipients. Conclusions. The t₉₀ calculated from the estimated and parameters was found to be a useful parameter for evaluating the stability of lyophilized -GA formulations. The prediction of t₉₀ by extrapolation was possible in the temperature range in which did not rapidly vary with temperature.     

Influence of age on the pharmacokinetics of vapiprost, a thromboxane A2 receptor antagonist, and platelet aggregation: comparison of pharmacokinetics by routine approach and population pharmacokinetics

The effects of a single-dose oral administration of a thromboxane A2 receptor antagonist, vapiprost (SN-309), on pharmacokinetic profile and inhibition of platelet aggregation were investigated in six healthy elderly volunteers (age: 65-72 years) and the influence of age on these parameters was studied by comparison with the results obtained in phase-I data involving healthy young participants. Although direct comparison of pharmacokinetic parameters was inappropriate because of different models, high Cmax and AUC values were obtained on comparison with the young. The inhibition of platelet aggregation in platelet rich plasma induced by U-46619 or collagen was rapidly established and remained suppressed for more than 8 h, although the effect was short-acting compared with the inhibition period in the young. This suggests that dose adjustment in the elderly is unnecessary In addition to a routine pharmacokinetic approach to determine the time-profile of vapiprost, population pharmacokinetics were studied using data from 51 volunteers in five clinical trials including the two above-mentioned studies. By fitting 812 plasma-monitoring points into the two-compartment model, the effects of several factors including age on parameters were investigated, based on the nonlinear mixed effect model. Clearance in the elderly attenuated 82.2% of that in the young, the distribution volume varied with platelet counts and delayed absorption was observed in volunteers with, rather than without, food intake. Closer bridging studies with other countries have resulted in the current local situation of abbreviating phase-III studies. Consequently to clarify the pharmacokinetic profile of the elderly in Japan and other countries, the population pharmacokinetics approach based on the data in the various phase I-II trials is useful.     

17 Beta-estradiol increases nitric oxide and prostaglandin I2 production by cultured human uterine arteries only in histologically normal specimens

These experiments were designed to investigate whether 17beta-estradiol (E2) modulates the endothelial function of perimenopausal human uterine arteries. After the artery specimen was cultured in the presence or absence of E2 at a physiologic concentration of 200 pg/ml, changes in isometric tension and cyclic nucleotide production were determined. Degree of intimal hyperplasia was assessed histologically and expressed as intima-to-media ratio. Acetylcholine produced an endothelium-dependent relaxation in six specimens (group I) of 12, which was inhibited by NG-nitro-L-arginine or indomethacin. However, the agonist failed to produce a definite relaxation in the remaining 6 (group II). The endothelium-dependent relaxation was significantly augmented after incubating with E2 only in group I specimens. Cyclic nucleotide production was significantly increased after E2 incubation only in group I specimens, whereas it was inhibited by NG-nitro-L-arginine or indomethacin. Histologic study revealed that the six specimens of group I had normal intima (intima-to-media ratio = 19.1+/-1.8%) and the remaining six of group II had intimal hyperplasia (intima-to-media ratio = 53.6+/-5.3%). Increased production of cyclic nucleotides occurred in uterine arteries with normal intima but not in arteries with intimal hyperplasia derived from perimenopausal women.     

Usefulness of the Kohlrausch-Williams-Watts Stretched Exponential Function to Describe Protein Aggregation in Lyophilized Formulations and the Temperature Dependence Near the Glass Transition Temperature

Purpose. We studied the feasibility of using the Kohlrausch-Williams-Watts stretched exponential function (KWW equation) to describe protein aggregation in lyophilized formulations during storage. Parameters representing mean aggregation time (_a) and stretched exponential constant (_a) were calculated according to the KWW equation by assuming that the time required for protein molecules to aggregate () varies because of the fact that protein aggregation occurs at a rate that depends on the degree of protein deformation resulting from stresses created during freeze-drying. The temperature dependence of the parameters near the glass transition temperature was examined to discuss the possibility of predicting protein aggregation by accelerated testing. Methods. Protein aggregation in lyophilized bovine serum -globulin (BGG) formulations containing dextran or methylcellulose, at temperatures ranging from 10 to 80°C, was followed by size-exclusion chromatography. Results. Non-exponential BGG aggregation in lyophilized formulations could be described by the KWW equation. The _a and _a parameters changed abruptly around the NMR relaxation-based critical mobility temperature for formulations containing dextran and methylcellulose. In the glassy state, in contrast, the _a parameter of these formulations exhibited continuous temperature dependence. The parameter , as calculated from _a and _a, reflected differences in values between the two excipients. Conclusions. The results indicate that the parameter _a is reflective of physical changes wihtin lyophilized formulations. Within the temperature range, during which no abrupt changes in _a were observed, knowledge regarding the _aand _a parameters allows the rate of protein aggregation to be predicted. The parameter was found to be useful in comparing the protein aggregation behavior of formulations having different _a and _a values.