Gabapentin--a new antiepileptic agent

Gabapentin is a new antiepileptic drug. Its mechanism of action is not clearly understood, but it seems to differ from that of other antiepileptic drugs. The favourable pharmacokinetic properties of gabapentin make it simple to use. Our preliminary clinical observations with gabapentin at the National Center for Epilepsy are presented. 58 adult patients (mean age 28.9 years), mainly with refractory partial seizures, had gabapentin added to their existing medication. The follow-up period was 6.9 months on average. Only one patient experienced a reduction in seizures of more than 50%, while 25 patients experienced a moderate reduction in seizures (10-50%). The clinical effect was most favourable in patients with secondary generalized tonic-clonic seizures. Gabapentin was well tolerated, and no clinically significant interactions were encountered. Recent observations show that the doses of gabapentin used in our study may have been too low.     

Alcohol-induced expression of the CD14 endotoxin receptor protein in rat Kupffer cells

Gut-derived endotoxins (lipopolysaccharide, LPS) are believed to contribute to alcohol-induced liver disease (ALD) by stimulating Kupffer cells, the resident liver macrophages, to release proinflammatory cytokines. This activation is largely mediated by CD14, a high-affinity membrane-anchored receptor for LPS. We observed, by chemiluminescence-enhanced detection, an increase in immunoreactive CD14 protein in Kupffer cells isolated from rats treated with ethanol for 2 weeks. Immunocytofluorescence experiments confirmed that this increase was confined to the membranes of Kupffer cells from the alcohol-treated rats. The increase was regulated pretranslationally: a 3-fold elevation (p < 0.01) in the hepatic level of CD14 mRNA was observed. The marked increase in CD14 expression suggests a new mechanism by which alcohol increases the LPS-mediated cytokine signaling by the liver macrophages, thus promoting the interaction between alcohol and endotoxins in the development of liver damage.     

Cortical and hippocampal volume deficits in temporal lobe epilepsy

PURPOSE: To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE). METHODS: Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA). RESULTS: As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe. CONCLUSIONS: Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.     

Detecting vascular problems in patients with diabetes treated with an intra-aortic balloon pump

Individuals with diabetes are at increased risk for both peripheral vascular disease and coronary artery disease. In patients with severe coronary artery disease, a cardiac assist device called an intra-aortic balloon pump (IABP) often is used to aid the failing heart and prevent further cardiac ischemia. Because this device is inserted via the femoral artery, patients are at risk of limb ischemia distal to the insertion site. Patients with diabetes are particularly prone to this complication. Detecting the early signs and symptoms of ischemia is crucial to preventing serious sequelae. Standard vascular examination techniques, in addition to being subjective and not easily reproducible, may be misleading in patients with diabetes. This article provides a review of the signs and symptoms of lower limb ischemia and noninvasive vascular tests that clinicians can use to evaluate lower extremity circulation. Also included are protocols for patient care during and after hospitalization, and two case studies of cardiac patients with diabetes who were treated with an IABP.     

Organization and development of facial motor neurons in the kreisler mutant mouse

The adult facial nerve contains the axons from two populations of efferent neurons. First, the branchiomotor efferent neurons that innervate the muscles of the second arch. These neurons project out of the hindbrain in the motor root and form the facial motor nuclei. Second, the preganglionic efferent neurons that innervate the submandibular and pterygopalatine ganglia. These neurons project from the hindbrain via the intermediate nerve and form the superior salivatory nucleus. The motor neurons of the facial nerve are known to originate within rhombomeres 4 and 5. In the kreisler mouse mutant there is a specific disruption of the hindbrain rhombomeres 5 and 6 appear to be absent. To investigate changes in the organization of the facial motor neurons in this mutant, we have used lipophilic dyes to trace the facial motor components both retrogradely and anterogradely. As expected, facial motor neurons are missing from rhombomere 5 in this mutant. In addition, the loss of these neurons correlates with the specific loss of the superior salivatory nucleus. In contrast, the branchiomeric neurons, that originate in rhombomere 4, appear to develop normally. This includes the caudal migration of their cell bodies forming the genu of the facial nerve. Our studies confirm that rhombomeres are critical to hindbrain development and that they are the fundamental unit at which motor neurons are specified.     

Inhibition of vascular smooth muscle cell growth by inhibition of fibronectin matrix assembly

The regulation of vascular smooth muscle cell (VSMC) proliferation by the fibronectin matrix was tested by treating human umbilical artery smooth muscle cells (HUASMCs) with a recombinant fragment of fibronectin (protein III1-C) that has previously been shown to modulate fibronectin matrix assembly. III1-C inhibited HUASMC proliferation by 75% to 90%. The inhibition of growth was time dependent; III1-C had no effect on DNA synthesis after 0 to 5 hours of treatment but did have an effect at 24 hours and beyond. III1-C did not stimulate apoptosis in these cells, indicating that the inhibition of proliferation was not due to an induction of programmed cell death. The effects of III1-C on cell growth were only specific for normal diploid smooth muscle cells. III1-C had no effect on the proliferation of IMR-90 fibroblasts, endothelial cells, NIH 3T3 cells, or the rat aortic smooth muscle cell line A7r5. However, III1-C did inhibit proliferation by primary rat aortic smooth muscle cells. An analysis of HUASMC fibronectin receptor (integrin alpha5beta1) distribution revealed that III1-C did not inhibit alpha5beta1 localization to focal contacts. Moreover, III1-C had no effect on the relative expression levels of seven different integrin subunits on HUASMCs. However, III1-C did inhibit fibronectin matrix assembly by rat aortic smooth muscle cells, HUASMCs, A7r5 cells, IMR-90 cells, and endothelial cells. An analysis of fibronectin synthesis indicated that the inhibition of fibronectin matrix assembly by III1-C was not due solely to a decrease in fibronectin synthesis. Finally, treatment of HUASMCs with anti-fibronectin monoclonal antibody L8 (which is known to inhibit fibronectin matrix assembly) also decreased the rate of HUASMC DNA synthesis. These results demonstrate that III1-C inhibits VSMC proliferation and suggest that this effect may be mediated by the inhibition of fibronectin matrix assembly.     

Co-administration of polyanions with a phosphorothioate oligodeoxynucleotide (CGP 69846A): a role for the scavenger receptor in its in vivo disposition

The effects of co-administering polyanions on the pharmacokinetics of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A), and the role of scavenger receptors in its in vivo disposition, have been investigated. Following i.v. administration, CGP 69846A was rapidly cleared from the plasma and distributed amongst high (e.g. kidney, liver, spleen), low (e.g. skeletal muscle) and negligible (e.g. brain) accumulating tissues. In addition it was shown that: 1) dextran sulphate co-administration has a dose-dependent effect on the disposition of CGP 69846A; 2) CGP 69846A undergoes renal filtration and renal accumulation largely results from tubular reabsorption; 3) cross-inhibition studies are consistent with CGP 69846A being recognized by scavenger receptors in vitro and in vivo; and 4) the scavenger receptor may be an important determinant for the in vivo disposition of CGP 69846A in mice. These studies contribute toward an increased understanding of the mechanism underlying the pharmacokinetic behaviour of phosphorothioate oligodeoxynucleotides.