Preliminary Report on Teratogenic Effects of Zonisamide in the Offspring of Treated Women with Epilepsy

Summary: Purpose: We wished to assess the risk of terato-genicity of zonisamide (ZNS) in humans.
Methods: Pregnant epileptic women treated with ZNS and their offspring were prospectively monitored from June 1989 to December 1994. The outcome of pregnancy and status of neonates were examined based on the same standardized protocol.
Results: Twenty-six offspring exposed to ZNS with or without other antiepileptic drugs (AEDs) were studied. Malformations were detected in 2 offspring (7·7%) exposed to ZNS polypharmacy. Anencephaly was detected in one case at 16 weeks of gestation (case 1, artificial abortion), and atrial septa1 defect was detected in another case at 37 weeks of gestation (case 2, delivery by cesarean section). Serum concentrations of ZNS during the first trimester of pregnancy were 6·1 μg/ml in case 1 and 6·3μ/ml in case 2; in both cases, the levels were below the therapeutic concentration range of ZNS.
Conclusions: Teratogenic effects of ZNS were not clearly defined from these results since malformations were detected in two polypharmacy cases but not in four monopharmacy cases. The present data do not indicate that the risk of ZNS teratogenicity is greater than that of other conventional AEDs. However, such risk cannot be neglected even at therapeutic dosages or concentrations of ZNS, especially in patients receiving polypharmacy.     

Glutamate immunoreactive terminals in the lateral amygdaloid nucleus: a possible substrate for emotional memory.

The ultrastructure and synaptic associations of terminals immunoreactive for L-glutamate (Glu) were examined in the lateral nucleus of the amygdala (AL). All results reported here involved tissue fixed only with paraformaldehyde. The specificity of the antiserum with paraformaldehyde fixation conditions was assessed and confirmed by immuno-dot blot analysis: the reactivity of anti-Glu to glutamic acid was at least 1,000 times greater than the reactivity to other amino acids. At the light microscopic level, Glu-immunoreactive punctate processes and somata were present in AL. At the electron microscopic level, many Glu-immunoreactive terminals were identified. Data analysis was performed on 365 of these labeled terminals. Glu-immunoreactive terminals were 0.3-1.5 microns in diameter and contained numerous small, clear vesicles as well as mitochondria. Many (77%) of the terminals analyzed had morphologically identifiable synaptic specializations. Most (90%) of the Glu-immunoreactive terminals with synaptic specializations formed asymmetric synapses on spines or small dendrites; synaptic specializations on soma or proximal dendrites were rarely seen (< 1%). Glu-immunoreactive terminals were qualitatively compared to terminals in AL labeled with two other antisera: anti-glutaminase, a marker for the enzyme that catalyzes the conversion of glutamine to the releasable or transmitter form of Glu, and anti-gamma-aminobutyric acid (anti-GABA), a marker for the major inhibitory amino acid transmitter in the brain. Terminals immunoreactive for glutaminase, like those immunoreactive for Glu, formed mostly asymmetric synaptic specializations on spines or small dendrites. In contrast, GABA-immunoreactive terminals usually formed symmetric synapses on soma or proximal dendrites and were never observed to form asymmetric axo-spinous contacts. Although Glu is a metabolic precursor to GABA, these data indicate that the majority of Glu-immunoreactive terminals reflect the site of synthesis and release of Glu and not of GABA. In addition, these results provide morphological evidence that Glu plays a role in excitatory neurotransmission at synapses in AL and support the growing body of data implicating excitatory amino acid-mediated synaptic plasticity in-emotional learning and memory processes in AL.     

A case of immunohistochemically carcinoembryonic antigen producing cervical cancer--the evaluation of plasma CEA levels in 201 patients with uterine cancer

A case of a cervical cancer in a 40-year-old woman with a plasma carcinoembryonic antigen (CEA) level of 29.4 ng/ml was investigated using light and electron microscopy. In addition, the plasma CEA levels before treatment were determined in 168 patients with cervical cancer and in 33 patients with endometrial cancer. CEA was found to be elevated in the plasma of 19% of those with cervical cancer and in 6% of those with endometrial cancer. Effective serial plasma CEA determinations following therapy, in patients whose plasma or tumors initially contain elevated amounts of antigen, might be useful as an adjunctive method in the earlier detection of a recurrent cancer.     

Iron deposition in cranial bone marrow with sickle cell disease: MR assessment using a fat suppression technique

Thirteen patients with sickle cell disease (SCD) undergoing transfusion therapy and 8 control patients were examined by magnetic resonance imaging to discriminate bone marrow change due to iron deposition from hematologic marrow hyperplasia. Using T1-weighted spin echo images, only two subjects showed extremely low signal intensity marrow compatible with iron deposition. However, using T2-weighted fast spin echo images with fat suppression, cranial bone marrow in SCD patients with transfusion therapy showed considerably lower signal than that of controls. The main cause of marrow signal decrease in SCD patients with transfusion therapy was considered to be iron deposition due to repeated transfusion therapy rather than red marrow hyperplasia.     

Activity-dependent survival and enhanced turnover of calcium in cultured rat cerebellar granule neurons

Neurons survive when their activity is maintained. An influential hypothesis on the cellular mechanism underlying this phenomenon is that there is an appropriate range of intracellular Ca²⁺ concentration ([Ca²⁺]i) for survival. The rat cerebellar granule neuron in culture serves as the most often used model system for the analysis of activity-dependent survival, since it does not survive unless an excitant (KCl or glutamate) is added to the culture medium. Against the above-mentioned hypothesis, we found in our previous examination no difference between steady-state [Ca²⁺]i in granule neurons cultured under high KCl (i.e., survival) and low KCl (i.e., death) conditions. In this report, we present the quantitative background of unchanged [Ca²⁺]i between the two culture conditions. Influx of Ca²⁺ due predominantly to L-type voltage-dependent calcium channels was higher in high KCl cultures than in low KCl cultures. At the same time, efflux of Ca²⁺ due to the activity of Ca²⁺/Na⁺ antiport was also higher in high KCl cultures. Additionally, we found that the endocytotic activity was greater in high KCl cultures than in low KCl cultures, as monitored by the rate of uptake of horseradish peroxidase added to medium. Since the uptake was blocked by an internal Ca²⁺ chelator, the increased endocytotic activity in high KCl cultures might be a consequence of the enhanced Ca²⁺ turnover.     

Reversal of multidrug resistance by new dihydropyridines with lower calcium antagonistic activity

Summary BS compounds, a series of new dihydropyridines, successfully overcame multidrug resistance in P388/ADR cells in vitro. These agents synergistically potentiated the cytotoxicity of Adriamycin to P388/ADR cells at a concentration of 1–2 M, whereas they showed hardly any synergistic effect in the parental cell line (P388/S) at the same concentration. They inhibited the active drug efflux in P388/ADR cells as well as the binding of [G-³H]-vinblastine to membrane vesicles from P388/ADR, which was increased in resistant P388 cells as compared with parental cells. Besides, unlike the activity of clinically used calcium antagonists, the calcium antagonistic activity associated with BS compounds was very weak: their arterial relaxation activity was <21% of that of verapamil. These data suggest that BS compounds specifically overcome multidrug resistance without the serious hypotensive side effects that accompany the use of verapamil orother calcium antagonists.     

Diazepam reduces both arterial blood pressure and muscle sympathetic nerve activity in human

It is known that benzodiazepines have a hypotensive effect, but the mechanism has not been well elucidated yet. To clarify whether this effect is due to central or peripheral mechanism, we administered 5 mg of diazepam or saline intravenously to healthy volunteers and assessed the change in blood pressure, heart rate, muscle sympathetic nerve activity and heart rate variability. After diazepam administration, systolic and mean blood pressure decreased significantly. Muscle sympathetic nerve activity was also significantly reduced but heart rate did not change, whereas the variables of spectral analysis of heart rate variability did not show significant change. We concluded that the hypotensive effect of diazepam in human is mainly due to the central mechanism.     

Immunosuppressive effect of restraint stress on the initiation of allergic rhinitis in mice

BACKGROUND: Exposure to acute stressors modulates both innate and acquired immune function. However, little is known about whether stress has the potential to modulate the pathogenesis of allergic rhinitis. OBJECTIVES: To determine the effects of acute restraint stress on the initiation of allergic rhinitis in a murine model. METHODS: CBA/J mice were repeatedly intranasally sensitized with phospholipase A2 (PLA2) from honeybee venom without adjuvant. Restraint stress was applied using uniform cylinders once a week for a continuous 8-hour period, on five occasions in total. Production of PLA2-specific antibodies and degree of nasal and blood eosinophilia were compared between stressed and control mice. RESULTS: Repeated intranasal sensitization with PLA2 induced PLA2-specific IgE and marked eosinophilia in both the nose and blood in CBA/J mice. Exposure to restraint stress significantly inhibited production of PLA2-specific IgE, IgG1 and IgG2a. Conversely, the stress exerted no significant effect on eosinophilia. CONCLUSIONS: Exposure to acute restraint stress inhibits antigen-specific antibody production, but not local or systemic eosinophilia. The results of this study suggest that acute stress has the potential to modulate the initiation of allergic rhinitis.     

Blepharophimosis sequence and de novo balanced autosomal translocation [46, XY,t(3;4)(q23;p15.2)]: Possible assignment of the trait to 3q23

We report on a boy with the blepharophimosis sequence and de novo, apparently balanced reciprocal translocation between 3q23 and 4p15.2 [46, XY,t(3;4)(q23;p15.2)de novo]. Possible assignment of this autosomal dominant disorder is discussed. A 3q23 band is a more preferable gene locus of the blepharophi mosis sequence, based on the comparison of clinical manifestations between 4p- and 3q-syndromes.