Stria terminalis axons ending on substance P and neurotensin-containing cells of rat central amygdaloid nucleus: An electron microscopic immunocytochemical study

Immunocytochemistry at the electronmicroscopic level was used to identify and examine substance P and neurotensin-containing perikarya and dendrites in the central amygdaloid nucleus of the rat. Following unilateral transection of the stria terminalis between the bed nucleus of the stria terminalis and the amygdala, degenerated nerve terminals were present in the ipsilateral central amygdaloid nucleus. These degenerated boutons were associated with both perikarya and dendrites of substance P and neurotensin-positive cells as well as unlabeled neurons.     

Simultaneous characterization of pre- and postsynaptic neuron contact sites in brain.

The combined application of electron microscopic study of nerve degeneration and immunocytochemical techniques enables both pre- and postsynaptic structures of central nervous system synapses to be characterized simultaneously. Information obtained from a model experiment is presented to indicate the usefulness of the method. After the surgical transection of the ventral noradrenergic bundle in rats, degenerating boutons of brainstem axons were demonstrated on luteinizing hormone-releasing hormone-positive and adrenocorticotropic hormone-positive neurons in the hypothalamic arcuate nucleus.     

CNS changes in hyperbilirubinemia. Functional implications

Hyperbilirubinemia is a recognized etiologic factor in motor and hearing disorders associated with cerebral palsy. Its role in more subtle forms of neurological impairment is more controversial. Using a mutant animal model, which develops symptoms and signs closely resembling the human kernicterus syndrome, neurons of hippocampus, cerebral cortex, cochlear nuclei, losuc ceruleus, and olfactory bulb were examined by electron microscopy. Pathological changes, observed in all areas studied, consisted of mitochondrial and endoplasmic enlargement and vacuolation, with glycogen deposition; increased extracellular space; myelin figures; and degenerating changes in nerve terminals. If we make the assumption that pathologic changes in the human infant with neonatal jaundice are similar to changes in the animal model, then the widespread involvement of CNS neurons in all cortical areas examined may well help to explain the syndromes of minimal cerebral dysfunction reported in clinical studies.     

3-Halohydantoins as halolactonization reagents

By the reaction of 15 with 3-halohydantoins (4–14) in N,N-dimethylformamide, which were prepared from corresponding hydantoins, 3-bromo-5,5-dimethylhydantoin was found to be the most convenient reagent for halolactonization reaction.     

Novel aspects of bromolactonization reaction using N-haloimides in an aprotic polar solvent

Depending upon the results obtained by the bromolactonization of olefinic acids (9–11) by means of N-bromosaccharin (4), the influence of the stabilities of the imidic anions resulted from heterolytic cleavage of N-haloimides, such as N-bromosuccinimide (1), N-bromophthalimde (2), and N-bromosaccharin (3) in dry N,N-dimethylformamide on the reactivity is elucidated.     

Innervation of the mitral valve is strikingly depleted with age.

Previous reports demonstrated that mammalian atrioventricular (AV) valves possess a dense nerve plexus, consisting of nerve subpopulations which differ from each other in densities and patterns of distribution in the valves, and which may have sensory or motor roles in valve function. Although there is extensive evidence that age-related changes occur in autonomic nerves of animals and humans (Daly et al. J. Pharm. Exp. Ther., 1988;245(3):798-803; Ingall et al. Aust. NZ J. Med., 1990;20:570-577; Tumer et al. Exp. Gerontol., 1992;27:301-307), and that these changes contribute to changes in cardiac function (Klausner and Schwartz Clin. Geriat. Med., 1985;1(1):119-114), there is little information about age-related changes in heart valve innervation. In this study, we used acetylcholinesterase (AChE) histochemistry to localize and compare qualitative and quantitative changes in the innervation of the mitral valves in young adult and aged animals of three species. Young adult and aged guinea pigs, mice, and Wistar and Fischer 344 rats were anesthetized with Nembutal, the hearts removed, and the mitral valves dissected out and processed for AChE localization. Camera lucida drawings of the AChE-positive nerves in representative segments of valve cusps were made directly from slides; these drawings were digitized and subjected to computer-assisted image analysis to obtain quantitative information about nerve plexus density in the valves. All three animal species showed profuse AChE-positive innervation in the mitral valves of young adult animals, and decreases in the density of this innervation in aged animals. The most striking loss of innervation, compared to the young adult, occurred in the mitral valves of aged Fischer 344 rats, in which large regions of the valves appeared virtually devoid of nerves. Further studies are needed to investigate whether and to what extent age-related losses in heart valve innervation affect valvular structure and function.     

Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.

PURPOSE: To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer. PATIENTS AND METHODS: Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half-life (T1/2), and volume of distribution at steady state (Vss). RESULTS: CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P less than .001), a 38% decrease in total CL (P < .01), a > twofold increase in T1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels > 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles. CONCLUSIONS: High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.     

Plasticity of catecholaminergic terminals in rat paraventicular hypothalamic nucleus after 6-Hydroxydopamine lesion: an emphasis on bouton sizes and synaptic frequency

Catecholaminergic (CA) nerve terminals in the paraventicular hypothalamic nucleus (PVN) of adult rats were studied at 4, 21, 56 and 180 days after a single injection of 6-hydroxydopamine (6-OHDA) neurotoxin into the right lateral ventricle of the brain. We previously described and quantified the extent of CA terminal sprouting in the PVN after 6-OHDA lesions. For this communication we studied parameters, specifically the bouton sizes and the synaptic frequencies of CA terminals during the renewal process, and evaluated how changes of these parameters are ralated to axonal sprouting. The CA boutons were identifiable in the electron microscope by exhibiting small granular vesicle (SGVs) after central administration of 5-hydroxydopamine (5-OHDA) marker. The marked CA boutons were measured and further categorized according to whether or not they were associated with distinct synaptic specializations at various post-lesion stages. The average sizes of CA boutons were strikingly similar in their diameters (1.0 υm) for both control and experimental tissues. However, CA boutons larger than 2.1 υm were rare and seen more often in the experimental tissues with 6-OHDA lesion and were sustained up to 180 days after lesions. Catecholaminergic profiles with ultrastructural features of growth cones were also seen in the PVN following the 6-OHDA lesions, indicating that there is growth activity in the PVN after 6-OHDA lesion. There were 33% of CA boutons in the PVN from the control tissues that appeared to have contacts. Four days after lesions with a significant reduction of CA terminals, the synaptic frequency was seen on 31% of surviving CA terminals; this synaptic frequency (31%) is close to that observed before lesioning. Of the CA boutons, 42% possessed synaptic contacts at both 21 and 56 days postlesion. At these stages there is still limited regeneration of CA terminals. At 180 days afler lesions with a significant CA terminal restoration, the synaptic frequency of CA boutons had dropped to 36%, a value closer to the control level. The following conclusions can be drawn: (1) the synaptic frequency of CA terminals 4 days afler lesions resembles that of controls, suggesting that synaptic contacts found at this short survival period are those CA terminals escaped from 6-OHDA destruction, not from regenerating fibers; (2) a higher synaptic frequency was exhibited by CA terminals at 21 and 56 days after lesions; by 180 days after the lesion; a subsequent decrease of synaptic frequency was observed on CA terminals, indicating synaptic plasticity of CA terminals; and (3) CA stumps in the PNV are able to extend to establish their synaptic contacts at a frequency close to control levels by 180 days after 6-OHDA lesion, suggesting that regenerative fibers may be functional.