Biomedical subjects
Publications and source records attributed to J M Williamson.
Most salivary gland tumours present with an obvious mass and are usually diagnosed clinically. We present a case of occult adenoid cystic carcinoma of the parotid which, due to its peculiar septal pattern of growth and complicated clinical setting, defied diagnosis for several years.
Past work has demonstrated a reduction of stimulus-evoked inhibitory input to hippocampal CA1 pyramidal cells in chronic models of temporal lobe epilepsy (TLE). It has been postulated that this reduction in inhibition results from impaired excitation of inhibitory interneurons. In this report, we evaluate the connectivity of area CA1 interneurons to their excitatory afferents in hippocampal-parahippocampal slices obtained from a rat model of chronic TLE. Rats were made chronically epileptic by a period of continuous electrical stimulation of the hippocampus, which establishes an acute condition of self-sustained limbic status epilepticus (SSLSE). This period of SSLSE is followed by a development of chronic recurrent spontaneous limbic seizures that are associated with chronic neuropathological changes reminiscent of those encountered in human TLE. Under visual control, whole cell patch-clamp recordings of interneurons and pyramidal cells were obtained in area CA1 of slices taken from adult, chronically epileptic post-SSLSE rats. Neurons were activated by means of electrodes positioned in stratum radiatum. Intrinsic membrane properties, including resting membrane potential, action potential (AP) threshold, AP half-height width, and membrane impedance, were unchanged in interneurons from chronically epileptic (post-SSLSE) tissue compared with control tissue. Single stimuli delivered to stratum radiatum evoked depolarizing excitatory postsynaptic potentials and APs in interneurons, whereas paired-pulse stimulation evoked facilitation of the postsynaptic current (PSC) in both control and post-SSLSE tissue. No differences between interneurons in control versus post-SSLSE tissue could be found with respect to the mean stimulus intensity or mean stimulus duration needed to evoke an AP. A multiple linear regression analysis over a range of stimulus intensities demonstrated that a greater number of APs could be evoked in interneurons in post-SSLSE tissue compared with control tissue. Spontaneous PSCs were observed in area CA1 interneurons in both control and post-SSLSE tissue and were markedly attenuated by glutamatergic antagonists. In conclusion, our data suggest that stimulus-evoked and spontaneous excitatory synaptic input to area CA1 interneurons remains functional in an animal model of chronic temporal lobe epilepsy. These findings suggest, therefore, that the apparent decrease of polysynaptic inhibitory PSPs in CA1 pyramidal cells in epileptic tissue is not due to a deficit in excitatory transmission from Schaffer collaterals to interneurons in stratum radiatum and straum oriens.
Estimation of interrater agreement for ordered categorical data is examined when the same sample is being assessed by various raters with different methods. We investigate the use of a latent model proposed by Qu, Piedmonte, and Medendorp (1995, Biomerics 51, 268-275) to estimate the correlation between raters for each method, and test for their equality. For each of the assessment methods, these correlations can be interpreted as the variance components of random effects representing subject and rater. This method is applied to an HIV study, in which the amount of ectopy on a woman's cervix is measured by both direct visual assessment and a computer planimetry method.
The Wiskott-Aldrich syndrome (WAS) is an X-linked (Xp11.22) recessive immunodeficiency syndrome characterized by susceptibility to opportunistic and pyogenic infections, thrombocytopenia, and eczema. Previous studies of obligate carriers of WAS documented that nonrandom inactivation of the X chromosome carrying the defective gene is observed in all peripheral blood cells. The existence of both abnormal platelets and lymphocytes is consistent with a defect that affects early hematopoietic precursors. We isolated CD34+ hematopoietic progenitor cells collected from obligate carriers of WAS by apheresis and used polymerase chain reaction analysis of a polymorphic variable number of repeats (VNTR) within the X-linked androgen receptor to document nonrandom inactivation. These data show that nonrandom inactivation of the X-chromosome in WAS-obligate carriers occurs early during hematopoietic differentiation.
Somatostatin-, neuropeptide Y-, neurokinin B- and cholecystokinin-containing neurons were investigated in the rat hippocampus in two chronic models of temporal lobe epilepsy, i.e. 30 days after rapid kindling or electrically induced status epilepticus (post-status epilepticus). After rapid kindling, somatostatin immunoreactivity was strongly increased in interneurons and in the outer and middle molecular layer of the dentate gyrus. In four of six post-status epilepticus rats (status epilepticus I rats), somatostatin immunoreactivity was slightly increased in the dorsal but decreased in the ventral dentate gyrus and molecular layer. Somatostatin immunoreactivity decreased in neurons of the dorsal hilus in the two other post-status epilepticus rats investigated, while a complete loss was found in the respective ventral extension (status epilepticus-II rats). These changes were associated with a different extent of neurodegeneration as assessed by Nissl staining. Similarly, neuropeptide Y immunoreactivity was enhanced in neurons of the hilus and in the middle and outer molecular layer of the dentate gyrus in the dorsal hippocampus of rapidly kindled and status epilepticus-I rats. Neuropeptide Y and neurokinin B immunoreactivity was enhanced in the mossy fibers of all post-status epilepticus rats, but not in the rapidly kindled rats. In status epilepticus-II rats, neuropeptide Y-and neurokinin B-positive fibers were also detected in the infrapyramidal region of the stratum oriens of CA3 and in the inner molecular layer of the dentate gyrus in the dorsal and ventral hippocampus respectively, labeling presumably sprouted mossy fibers. Increased staining of neuropeptide Y and neurokinin B was found in the alveus after rapid kindling. Cholecystokinin immunoreactivity was markedly increased in the cerebral cortex, Ammon's horn and the molecular layer of the dentate gyrus in the ventral hippocampus of rapidly kindled and post-status epilepticus rats. The lasting changes in the immunoreactive pattern of various peptides in the hippocampus may reflect functional modifications in the corresponding peptide-containing neurons. These changes may be involved in chronic epileptogenesis, which evolves in response to limbic seizures.
The solution structure of the 39-residue peptide margatoxin, a scorpion toxin that selectively blocks the voltage-gated potassium-channel Kv1.3, has been determined by NMR spectroscopy. The toxin was isotopically labeled with 13C and 15N and studied using two-dimensional homonuclear and three- and four-dimensional heteronuclear NMR spectroscopy. The final structure was determined using 501 constraints, comprising 422 NOE constraints, 60 dihedral angle constraints, 9 disulfide constraints, and 10 hydrogen bond constraints. Structures were initially determined with the program PEGASUS and subsequently refined with X-PLOR. The average rms deviation from a calculated average structure for the backbone atoms of residues 3-38 is 0.40 A. A helix is present from residues 11 to 20 and includes two proline residues at positions 15 and 16. A loop at residues 21-24 leads into a two-strand antiparallel sheet from residues 25 to 38 with a turn at residues 30-33. Residues 3-6 run adjacent to the 33-38 strand but do not form a canonical beta-strand. The two additional residues of margatoxin, relative to the related toxins charybdotoxin and iberiotoxin, insert in a manner that extends the beta-sheet by one residue. Otherwise, the global structure is very similar to that of these two other toxins. The longer sheet may have implications for channel selectivity.
Kindling is widely accepted as a model of chronic epilepsy as well as a model of plasticity in the nervous system. Conventional kindling studies have used infrequent stimuli (separated by many hours) to establish a fully kindled state in which enhanced responses (kindled motor seizures and protracted afterdischarges) are consistently triggered by stimuli that initially did not elicit such responses. The enhanced responses occur even after a prolonged stimulus-free interval. Whereas the establishment of a kindled state with traditional stimulus protocols takes several weeks, our previous work showed that kindling could take place much more quickly when the interstimulus interval was set at 30 min (rapid kindling). In this report we tested whether rapid kindling protocols share with traditional kindling protocols the ability to establish a fully kindled state. Using different stimulus protocols involving recurrent hippocampal seizures, we characterized two types of kindling. 'Rapid kindling' developed over hours, but was transient, with a decay rate of a few days so that a fully kindled state did not persist. In contrast, 'slow kindling' developed over several weeks and was enduring, apparently permanent, being associated with a fully kindled state. These findings suggest that, while having certain similarities, the two types of kindling arise from dissimilar mechanisms. The existence of these two types of kindling has implications for epileptogenesis in humans. Moreover, the protocols developed in this work provide a useful means to control for the effects of seizures that are not related to mechanisms underlying a fully kindled state.
Kindling is a widely used model of epilepsy. While intriguing hypotheses have recently emerged about how kindling occurs, the mechanisms behind kindling remain to be elucidated. In order to test whether certain anatomical changes that have been detected in the brains of animals that have completed kindling are necessary for the expression of kindled seizures, means to achieve kindling over a time course too rapid for the anatomical changes to take place were sought. Stimulus trains of various durations (2 and 10 s) and frequencies (20, 50, and 100 Hz) were given every 30 min, 12 times a day for 4 consecutive days to rats through bipolar electrodes stereotactically positioned in the ventral hippocampus. Responses were monitored with conventional kindling behavioral seizure scores and afterdischarge durations. The frequencies studied were chosen to survey the range that has been previously used to determine the optimal frequency for eliciting maximal dentate activation. Maximal dentate activation is a paroxysmal process that has been postulated to play both a role in regulating epileptiform activity in the hippocampus and adjacent regions that are coupled in a functional hippocampal-parahippocampal loop and a role in kindling. All types of trains resulted in rapid kindling in which kindled motor seizures emerged after several stimuli and then were consistently elicited with each stimulus; there was also retention of the kindled state after periods of 18 h of withholding the stimuli. Thus, the overall response profile of the rapid kindling demonstrated in this study was phenomenologically similar to the profile of traditional kindling. Yet rapid kindling developed more quickly than did mossy fiber sprouting, determined in prior work, thereby excluding the latter as a necessary factor in rapid kindling. Stimulus frequency significantly influenced the rate of rapid kindling. Trains of 20 Hz, the optimal frequency for eliciting maximal dentate activation, yielded the fastest kindling. This finding supports the proposed role of maximal dentate activation and the hippocampal-parahippocampal loop in kindling. Longer (10 s) trains consistently triggered shorter afterdischarge durations. We postulate that this may reflect a tighter linkage between seizure-terminating processes with the 10 s trains than with 2 s trains.
Ectopic 'hamartomatous' thymoma is a rare benign neoplasm. These tumours are found in the neck and are thought to be part of a spectrum of ectopic cervical thymic neoplasia. The clinical and histological features are discussed and the literature is reviewed. An attempt is made to explain in embryological terms why such lesions appear to occur more commonly on the left side.
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Two patients are reported in whom initial misdiagnoses of medullary cancer or trabecular hyaline adenoma for papillary carcinoma were made.
The influence of electrical stimulus parameters on focal seizure production was studied. Stimulations and recordings were carried out with bipolar electrodes stereotactically positioned in the ventral hippocampus of kindled rats. After discharge thresholds were determined for stimulus trains with different combinations of train durations (0.5, 1, 2, 5, 10 s), intratrain frequencies (10, 20, 50, 60, 100 Hz), and pulse widths (0.5 and 1.0 ms). For a given combination of pulse width and intratrain frequency, thresholds decreased as train duration increased; the effect was profound with shorter durations but markedly attenuated with train durations > or = 5 s. For a particular train duration and pulse width, thresholds varied inversely with intratrain frequency; the degree of variation in the thresholds with frequency was greater the shorter the train. For the train durations studied, thresholds were lower with 1.0-ms pulses for intratrain frequencies > or = 20 Hz. However, for 10 Hz, the 0.5-ms pulses were more effective for 2-, 5- and 10-s trains. After discharge thresholds were found to also vary with the number of pulses in the stimulus trains. For stimuli with fewer pulses, thresholds were higher and showed marked variation with train duration, intratrain frequency, and pulse width. For stimuli with more pulses, thresholds fell to a lower limit and the influence of train duration was substantially lessened. This study provides a systematic examination of the influence of stimulus parameters on generation of focal seizures and should prove useful in designing and interpreting future experiments studying the neurobiology of seizures in the hippocampus and related structures and helpful in antiepileptic drug testing.
In urethane-anesthetized rats, a process termed maximal dentate activation has been shown to be associated with the lengthening of afterdischarges that occurs with repeated hippocampal stimulation. Maximal dentate activation is a unique paroxysmal form of epileptiform discharges consisting of large amplitude population spikes in the dentate gyrus. The current experiments examined the relationship of maximal dentate activation to kindling of motor seizures in the awake animal. Both long duration (5 or 10 s) and short duration (1 s) stimulus trains in either the hippocampus or the amygdala were effective in eliciting maximal dentate activation. Repeated stimulation of the amygdala produced lengthening of afterdischarges and kindling of motor responses, but only after maximal dentate activation had appeared in response to the stimulus. Over the course of amygdala kindling, the duration of maximal dentate activation lengthened with increasing severity of behavioral seizures. This evidence supports the hypothesis that maximal dentate activation is a marker for the presence of seizures distributed throughout limbic circuits. In addition, the data suggest that maximal dentate activation may be an important process involved in the acquisition of kindled responses.
This study examined the individual characteristics, family relations, and stress/social support of 50 maltreated adolescents and their mothers. Dyads were divided into 4 demographically similar groups: neglect, physical abuse, sexual abuse, and nonmaltreatment control. Results show that adolescent neglect was primarily associated with extrafamilial difficulties and social isolation. Adolescent physical abuse was linked more with rigidity in family relations, poorer maternal understanding of child developmental skills, and adolescent externalizing behaviors. In contrast, adolescent sexual abuse was related to maternal emotional problems and adolescent internalizing behaviors. In general, each group of maltreated adolescents experienced lower levels of family cohesion, more attention problems, and more daily stress than did their nonmaltreated counterparts. Findings are consistent with an ecological model of adolescent maltreatment.
Lipid A, the component of lipopolysaccharide that provides the membrane anchor of the core and O-antigen sugars, is known to contain characteristic R-3-hydroxy fatty acids bound to the 2,2' (N-linked) and 3,3' (O-linked) positions of the glucosamine disaccharide in different gram-negative bacteria. The studies reported here show that it is the acyl-acyl carrier protein specificities of the enzymes UDP-GlcNAc-O-acyltransferase and UDP-3-O-[(R)-3-hydroxyacyl]-GlcN-N-acyltransferase that determine the nature of these fatty acids.
Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.
Rubromycins, a class of quinone antibacterials, were discovered to selectively inhibit human immunodeficiency virus-1 (HIV-1) RNA-directed DNA polymerase (reverse transcriptase) (RT) activity more potently than cellular DNA polymerase alpha. beta- and gamma-rubromycin each inhibited equipotently HIV-1 RT and avian myeloblastosis virus RT, in a concentration-dependent manner, and were significantly weaker as inhibitors of calf thymus DNA polymerase alpha. These agents inhibited HIV-1 RT reversibly, were competitive with respect to template.primer, and were noncompetitive with respect to TTP. Dixon analyses yielded HIV RT Ki values of 0.27 +/- 0.014 and 0.13 +/- 0.012 microM for beta- and gamma-rubromycin, respectively. Similarly, using DNA polymerase alpha, the Ki values were 25.1 +/- 4.3 and 3.9 +/- 0.6 microM for beta- and gamma-rubromycin, respectively. Because these agents were toxic to noninfected human T lymphoid cells using concentrations at or above 6 microM, HIV-1 infectivity studies were carried out at 0.8-6 microM. At these concentrations, which are below the range expected to provide protection, no significant antiviral activity was observed. Although beta- and gamma-rubromycins did not possess sufficient HIV RT inhibitory potency or selectivity versus mammalian DNA polymerase to demonstrate antiviral activities, these studies support the hypothesis that specific molecules containing quinone functional groups can selectively inhibit viral polymerase activities over cellular polymerase activities. In addition, these studies suggest that rubromycins may be lead structures for the development of more potent and selective agents.
MK-801 is a new drug that produces a noncompetitive blockade at the subclass of glutamate receptors activated by N-methyl-D-asparate (NMDA). The antiepileptic properties of MK-801 were studied using kindled seizures as a model of complex partial seizures with secondary generalization. A test protocol was employed that allowed: (1) examination of the efficacy of MK-801 against several parameters that gauge different aspects of epileptogenesis; (2) determination of the time-action profile of these effects; and (3) examination of the toxicity of MK-801 in animals experiencing seizures. The drug was found to be potent against the spread of seizures but less effective against parameters linked to partial seizures. At the higher doses of the drug required to truncate hippocampal afterdischarges, considerable neurotoxicity was encountered. In addition, the antiepileptic effects of MK-801 showed a use dependence so that, at a given time after the drug was administered, a greater suppression of seizures was noted if there had been preceding seizures in the presence of the drug than if there had not been. These findings indicate that there may be limitations to the clinical utility of MK-801 as an antiepileptic agent and that the drug may provide greatest benefit when used for the suppression of seizure generalization and when seizures are closely spaced.