Successful treatment of supraventricular tachycardia exhibiting hydrops fetalis with flecainide acetate. A case report

BACKGROUND: The efficacy of flecainide acetate for the treatment of fetal supraventricular tachycardia with hydrops fetalis and changes in venous blood flow patterns in the fetus during treatment are reported. CASE: Oral flecainide administration was started at 30 weeks of gestation. Cardioversion was achieved 6 days after treatment. Sustained abnormal venous Doppler indices were shown and complete normalization of venous returns was observed 6 days after cardioversion. A vigorous male baby was born, and he is now 1 year of age and in good condition with no medication. CONCLUSION: Reversible cardiac dysfunction was observed even after cardioversion in the fetus with supraventricular tachycardia, which could be assessed precisely by venous Doppler analysis.     

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.     

Molecular Mobility of Protein in Lyophilized Formulations Linked to the Molecular Mobility of Polymer Excipients,as Determined by High Resolution 13C Solid-State NMR

Purpose. The mobility of protein molecules in lyophilized protein formulations was compared with that of excipient molecules based on the spin-lattice relaxation time (T₁) of each molecule determined by high resolution ¹³C solid-state NMR. The relationship between molecular mobility and protein stability is discussed. Methods. Protein aggregation of lyophilized bovine serum --globulin (BGG) formulation containing dextran was measured by size exclusion chromatography. The T₁ of the BGG carbonyl carbon and dextran methin carbon in the formulation was determined by high resolution ¹³C NMR, and subsequently used to calculate the correlation time (_C) of each carbon. The spin-spin relaxation time (T₂) of BGG and dextran protons was measured by pulsed NMR spectrometry, and the critical temperature of appearance of Lorentzian relaxation due to liquid BGG and dextran protons (T_mc) was determined. Results. The _C of dextran methin carbon in BGG-dextran formulations exhibited a linear temperature dependence according to the Adam-Gibbs-Vogel equation at lower temperatures, and a nonlinear temperature dependence described by the Vogel-Tamman-Fulcher equation at higher temperatures. The temperature at which molecular motion of dextran changed was consistent with the T_mc. The _C of BGG carbonyl carbon exhibited a similar temperature dependence to the _C of the dextran methin carbon and substantially decreased at temperatures above T_mc in the presence of dextran. The temperature dependence of BGG aggregation could be described by the Williams-Landel-Ferry equation even at temperatures 20°C lower than T_mc. Conclusions. High resolution ¹³C solid-state NMR indicated that the molecular motion of BGG was enhanced above T_mc in association with the increased global segmental motion of dextran molecules.     

Preattentive dysfunction in bipolar disorder: A MEG study using auditory mismatch negativity

Background

Neuropsychological studies have demonstrated that cognitive dysfunction represents pathophysiological mechanisms underlying bipolar disorder. However, information processing deficits in bipolar disorder have not often been examined electrophysiologically. Here, we examined preattentive processing and sensory information processing using mismatch field (MMNm) and P1m components, respectively, using magnetoencephalography.

Methods

Ten patients with bipolar disorder and 20 healthy volunteers participated in the study. The participants were presented with auditory stimuli sequences comprising standard and deviant stimuli. MMNm was elicited in response to changes in duration and frequency of pure-tone stimuli and a vowel across-category change.

Results

The magnetic global field power of MMNm in the right hemisphere under the pure-tone condition was significantly delayed in patients with bipolar disorder compared to healthy volunteers, and that of P1m did not differ between the two groups. The MMNm dipole in the left hemisphere was located inferior in patients with bipolar disorder than in healthy volunteers. This finding did not correlate with clinical symptoms.

Conclusions

Information processing at the preattentive level is impaired in patients with bipolar disorder irrespective of clinical symptoms, and this dysfunction is not due to sensory level dysfunction. The quality of preattentive information processing impairment is different between patients with bipolar disorder and patients with major depressive disorder, as shown by the MMNm latency and power differences.     

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.     

Evaluation of a novel kit (TF-Test) for the diagnosis of intestinal parasitic infections

Intestinal parasitic infections are currently a source of concern for Public Health agencies in developing and developed countries. Since three ovum‐and‐parasite stool examinations have been demonstrated to provide sensitive results, we designed a practical and economical kit (TF‐Test) that is now commercially available (Immunoassay Com. Ind. Ltda., São Paulo, Brazil). This kit allows the separate collection of three fecal specimens into a preservative solution. The specimens are then pooled, double‐filtered, and concentrated by a single rapid centrifugation process. The TF‐Test was evaluated in four different laboratories in a study using 1,102 outpatients and individuals living in an endemic area for enteroparasitosis. The overall sensitivity found using the TF‐Test (86.2–97.8%) was significantly higher (P<0.01) than the sensitivity of conventional techniques such as the Coprotest (NL Comércio Exterior Ltda, São Paulo, Brazil) and the combination of Lutz/Hoffman, Faust, and Rugai techniques (De Carli, Diagnóstico Laboratorial das Parasitoses Humanas. Métodos e Técnicas, 1994), which ranged from 48.3% to 75.9%. When the above combined three specimen technique was repeated with three specimens collected on different days, its sensitivity became similar (P>0.01) to that of the TF‐Test. The kappa index values of agreement for the TF‐Test were consistent (P<0.01), being higher and ranking in a better position than conventional techniques. The high sensitivity, cost/benefit ratio, and practical aspects demonstrate that the TF‐Test is suitable for individual diagnosis, epidemiological inquiries, or evaluation of chemotherapy in treated communities. J. Clin. Lab. Anal. 18:132–138, 2004. © 2004 Wiley‐Liss, Inc.     

Branch retinal artery occlusion and central retinal vein occlusion associated with pegylated interferon plus ribavirin combination therapy for chronic hepatitis C

A 62-year-old male treated with pegylated interferon α-2b plus ribavirin for chronic hepatitis C complained of sudden painless decreased visual acuity. This patient was diagnosed as having simultaneous occlusions of the branch retinal artery and central retinal vein, although he had no history of major risk factors for retinal vessel (artery and vein) occlusion. Unfortunately, visual acuity did not completely recover. Furthermore, the patient was heterozygous for interleukin (IL) 28B genetic polymorphisms. The etiology of interferon-associated retinal vessel occlusion is not yet clear. However, a review based on previous case reports suggested that some factors including ribavirin might act as a risk or cause of retinal vessel occlusion.     

The oestrogen metabolite 2-methoxyoestradiol alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancerous but not healthy cells of the human endometrium

Cancers of the reproductive tract account for 12% of all malignancies in women. As previous studies have shown that oestrogen metabolites can cause apoptosis, we characterised the effect of oestrogen and oestrogen metabolites on non-cancerous and cancerous human endometrial cells. Herein, we demonstrate that 2-methoxyoestradiol (2ME), but not 17beta-oestradiol, induces apoptosis in cancer cell lines and primary cultured tumours of endometrial origin. In contrast, 2ME had no effect on cell viability of corresponding normal tissue. This ability of 2ME to induce apoptosis does not require oestrogen receptor activation, but is associated with increased entry into the G2/M phases of the cell cycle and the activation of both the intrinsic and the extrinsic apoptotic pathways. The selective behaviour of 2ME on cancerous as opposed to normal tissue may be due to a reduction in 17beta-hydroxysteroid dehydrogenase type II levels in cancer cells and to a differential down-regulation of superoxide dismutase. Furthermore, we demonstrate that pre-treatment with 2ME enhances the sensitivity of reproductive tract cancer cells to the apoptotic drug tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), without the loss in cell viability to normal cells incurred by currently chemotherapeutic drugs. In conclusion, 2ME, alone or in combination with TRAIL, may be an effective treatment for cancers of uterine origin with minimal toxicity to corresponding healthy female reproductive tissue.