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D H Lowenstein

Publications and source records attributed to D H Lowenstein.

At least 19 recordsLinked to original sources
PubMed1992

Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures.

K+ channels are major determinants of membrane excitability. Differences in neuronal excitability within the nervous system may arise from differential expression of K+ channel genes, regulated spatially in a cell type-specific manner, or temporally in response to neuronal activity. We have compared the distribution of mRNAs of three K+ channel genes, Kv1.1, Kv1.2, and Kv4.2 in rat brain, and examined activity-dependent changes following treatment with the convulsant drug pentylenetetrazole. Both regional and cell type-specific differences of K+ channel gene expression were found. In addition, seizure activity caused a reduction of Kv1.2 and Kv4.2 mRNAs in the dentate granule cells of the hippocampus, raising the possibility that K+ channel gene regulation may play a role in long-term neuronal plasticity.

Animals↗
PubMed1992

Clinical and EEG features of status epilepticus in comatose patients.

We retrospectively evaluated the clinical and EEG features of status epilepticus (SE) in 47 comatose adult patients in whom SE was suspected clinically or because the EEG revealed repetitive electrographic seizures or continuous spike-and-wave activity. Three groups of patients were identified. Group-1 patients (n = 33) had SE both clinically and on EEG. They usually had subtle, clonic movements restricted to the eyes, face, and upper extremities, and the EEG most commonly showed repetitive electrographic seizures or continuous spike-and-wave activity. Group-2 patients (n = 9) also had subtle motor manifestations of seizures, but the EEG was not that of SE, consisting of either irregular slowing with frequent spikes and sharp waves, an irregular mixed-frequency background with episodic accentuation, or diffuse slowing; one patient also had an intermittent burst-suppression pattern. The five patients in Group 3 lacked any clinical signs of seizures, but the EEG showed repetitive electrographic seizures or continuous spike-and-wave activity. There were no significant differences between groups in etiology of SE, response to therapy, or outcome, and there was no obvious relationship between the EEG findings and duration of SE. We conclude that recognition of SE in comatose patients may require both clinical and EEG evaluation since either approach by itself may fail to establish the diagnosis. Furthermore, the EEG findings in established SE do not necessarily progress through the series of defined stages suggested by some authors.

Adolescent↗
PubMed1992

Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus.

Despite intensive study, the neurobiological basis of epilepsy and persistent memory impairment following traumatic head injury remains unknown. Since abnormalities of the hippocampus are known to be associated with temporal lobe seizures and memory dysfunction, we investigated the effects of experimental traumatic brain injury on hippocampal structure and function in the rat. Using a model of fluid-percussion injury, we have discovered that neurons of the dentate hilus are vulnerable to a brief, unilateral impact to the extradural surface of the brain. One week after trauma, there was a dramatic reduction in hilar neurons ipsilateral to the impact, and a milder but significant decrease in neurons on the contralateral side as well. This neuronal loss was highly selective since adjacent dentate granule and pyramidal neurons appeared relatively unaffected. Immunocytochemistry showed that the hilar cell loss included a loss of somatostatin-immunoreactive neurons, and degeneration stains provided evidence that irreversible hilar injury occurred within 4 hr of impact. To assess the functional effects of the hilar damage, dentate granule cell field potentials were measured in response to perforant path stimulation. This revealed abnormal dentate granule cell hyperexcitability at 2.0 Hz stimulation in many of the injured animals. The presence of abnormal hyperexcitability correlated with the loss of hilar neurons. Thus, a momentary impact to the surface of the brain can cause selective, bilateral hippocampal injury with associated abnormalities in dentate gyrus physiology. Furthermore, the pattern of cell loss is similar to that observed in some patients with temporal lobe epilepsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Heat shock protein expression in vulnerable cells of the rat hippocampus as an indicator of excitation-induced neuronal stress.

The inducible 72 kDa heat shock protein (HSP72) has been shown to be protective in non-neuronal cells and neurons in culture, but its function and the control of its expression in the CNS are poorly understood. Although HSP72 is induced in neurons in vivo by neurotoxic compounds that produce seizures and neuronal damage, it is unknown if its expression is a specific response to excitation per se or to "stressful" or potentially injurious excitation, or if it is a marker or mediator of irreversible injury. We have attempted to identify the nature of the stimulus for HSP72 expression by utilizing focal electrical stimulation that can either excite or destroy postsynaptic cells, depending on the duration of afferent stimulation. Previous studies have demonstrated that intermittent stimulation of the main hippocampal afferent pathway for 24 hr evokes synchronous discharges in dentate granule cells but does not injure them. However, the same stimulation irreversibly destroys three of the four cell populations innervated by the granule cells. The three vulnerable populations are the dentate hilar mossy cells, the somatostatin/neuropeptide Y (NPY)-immunoreactive hilar neurons, and the CA3c pyramidal cells. The fourth and relatively resistant population is the GABA-immunoreactive dentate basket cells. In this study, we have localized HSP72 expression immunocytochemically in the hippocampal dentate gyrus in response to nontoxic durations of potentially neurotoxic afferent stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Experimental pneumococcal meningitis causes central nervous system pathology without inducing the 72-kd heat shock protein.

We examined whether experimental pneumococcal meningitis induced the 72-kd heat shock protein (HSP72), a sensitive marker of neuronal stress in other models of central nervous system (CNS) injury. Brain injury was characterized by vasculitis, cerebritis, and abscess formation in the cortex of infected animals. The extent of these changes correlated with the size of the inoculum (P less than 0.003) and with pathophysiologic parameters of disease severity, i.e., cerebrospinal fluid (CSF) lactate (r = 0.61, P less than 0.0001) and CSF glucose concentrations (r = -0.55, P less than 0.0001). Despite the presence of numerous cortical regions having morphologic evidence of injury, HSP72 was not detected in most animals. When present, only rare neurons were HSP72 positive. Western blot analysis of brain samples confirmed the paucity of HSP72 induction. The lack of neuronal HSP72 expression in this model suggests that at least some of the events leading to neuronal injury in meningitis are unique, when compared with CNS diseases associated with HSP72 induction.

Animals↗
PubMed1991

Change in pattern of muscle activity following botulinum toxin injections for torticollis.

Twenty patients with torticollis had electromyographic studies of their neck muscles performed before and after a series of local injections of botulinum toxin. The pattern of muscle activity changed after the injections, and this effect persisted even after head position had returned to baseline. Patients who did not experience any clinical benefit from the injections also demonstrated a change in the pattern of muscle activity. These results suggest that the underlying abnormality in torticollis usually involves a general motor program for head position, rather than the activity of individual neck muscles.

Adult↗
PubMed1991

Up regulation of calbindin-D28K mRNA in the rat hippocampus following focal stimulation of the perforant path.

Calbindin-D28K is a constitutive Ca2(+)-binding protein expressed in hippocampal neurons that are resistant to various forms of excitotoxic injury. However, the local factors controlling calbindin-D28K expression within the central nervous system are unknown. We report that neuronal excitation via the perforant path leads to an increased expression of calbindin-D28K mRNA within dentate granule cells. This response is related specifically to stimulation that induces prolonged periods of bursting afterdischarges and precedes cellular injury. The up regulation of calbindin-D28K mRNA occurs during the type of neuronal activation associated with elevated cytosolic Ca2+ and suggests that the maintenance of Ca2+ homeostasis includes a system of feedback control at the level of gene expression.

Animals↗
PubMed1991

The stress protein response in cultured neurons: characterization and evidence for a protective role in excitotoxicity.

We used purified cultures of cerebellar granule cells to investigate the possible protective role of stress proteins in an in vitro model of excitotoxicity. Initial experiments used one- and two-dimensional polyacrylamide gel electrophoresis to confirm the induction of typical stress protein size classes by heat shock, sodium arsenite, and the calcium ionophore A23187. Immunoblot analysis and immunocytochemistry verified the expression of the highly inducible 72 kd heat shock protein (HSP72). Granule cell cultures exposed to glutamate showed evidence of cellular injury that was prevented by the noncompetitive NMDA antagonist MK-801, yet glutamate did not induce a detectable stress protein response. Nonetheless, preinduction of heat shock proteins was associated with protection from toxic concentrations of glutamate. These results imply that the HSP72 expression observed in in vivo models of excitotoxicity may not be directly related to the effects of excitatory amino acids. However, the ability of stress protein induction to protect against injury from glutamate may offer a novel approach toward ameliorating damage from excitotoxins.

Animals↗
PubMed1991

The temporal profile of 72-kDa heat-shock protein expression following global ischemia.

The potential role of the nonconstitutive 72-kDa heat-shock protein (HSP72) in selective neuronal vulnerability to ischemia was studied in rats subjected to graded global ischemia. Immunocytochemistry using a monoclonal antibody against HSP72 was performed on tissue collected after 24 hr of reperfusion. The appearance of HSP72 immunoreactivity correlated in a graded fashion with those regions known to be selectively vulnerable in ischemia. That is, HSP72 was induced in only hilar interneurons and CA1 pyramidal cells following brief ischemia. After intermediate durations of ischemia, HSP72 was expressed in the CA3 neurons and cortical layers 3 and 5, and after the longest intervals, HSP72 appeared in dentate granule cells. Heat-shock protein expression preceded cell death (assessed with acid fuchsin staining) in all regions. This temporal profile suggests that the capability of neurons to express HSP72 is unlikely to account for selective vulnerability of different brain regions following ischemia; its role in neuroprotection during ischemic injury in vivo remains unknown.

Animals↗
PubMed1990

Emergence of recreational drug abuse as a major risk factor for stroke in young adults.

OBJECTIVE: To investigate the clinical and epidemiologic relations between recreational drug abuse and stroke in young persons. DESIGN: A case-control study based on medical records. SETTING: San Francisco General Hospital, a 400-bed municipal hospital. PATIENTS: Consecutive sample of 214 patients aged 15 to 44 years, admitted between 1979 and 1988 with a diagnosis of ischemic or hemorrhagic stroke. An equal number of control patients admitted with diagnoses of status asthmaticus, acute appendicitis, or acute cholecystitis were matched to stroke patients by age, sex, and year of hospitalization. MEASUREMENTS AND MAIN RESULTS: Seventy-three patients with stroke (34%) were drug abusers compared with 18 (8%) of the controls. In 47 patients with stroke, temporal proximity of drug administration (n = 34) or infectious endocarditis (n = 13) suggested a direct association between drug abuse and stroke. After controlling for other identifiable stroke risk factors, the estimated relative risk for stroke among drug abusers compared with that among non-drug abusers was 6.5 (95% CI, 3.1 to 13.6), and this increased to 49.4 (CI, 6.4 to 379.0) for those patients whose symptoms began within 6 hours of drug administration. Among patients less than 35 years of age, drug abuse was the most commonly identified potential predisposing condition (47%), and it was the only condition with a significantly elevated relative risk for stroke (11.7; CI, 3.2 to 42.5). Further, a substantial rise in the proportion of drug-related strokes was observed in the last 3 years of the study (31% in 1986 to 1988, compared with 15% in 1979 to 1985, P = 0.008). Cocaine, especially recently, was the drug used most frequently in drug-related strokes. CONCLUSION: In an urban population such as ours, recreational drug abuse appears to be a prominent and growing risk factor for strokes in young adults.

Adolescent↗
PubMed1990

The pattern of 72-kDa heat shock protein-like immunoreactivity in the rat brain following flurothyl-induced status epilepticus.

The inducible 72-kDa heat shock protein (HSP72) is a highly conserved stress protein that is expressed in CNS cells and may play a role in protection from neural injury. We used a monoclonal antibody to HSP72 and immunocytochemistry to localize HSP72 in the rat brain 24 h following either 30 or 60 min of flurothyl-induced status epilepticus. Sprague-Dawley rats were anesthetized with halothane, paralyzed, and ventilated, and remained normotensive and well oxygenated for the duration of the seizures. Seizure activity was quantified via analysis of the scalp EEG pattern. HSP72-like immunoreactivity (HSP72-LI) was induced in specific brain regions in a graded fashion that correlated, in part, with the duration and degree of seizure activity. Milder seizures produced HSP72-LI limited to layers 2 and 3 of frontoparietal cortex, dentate hilus cells, and CA3 pyramidal neurons. More extensive seizures led to HSP72-LI in layers 2, 3 and 5 of frontoparietal and visual cortex, dentate hilus cells, CA1 and CA3 pyramidal neurons, and certain thalamic and amygdaloid nuclei. These are similar to many, but not all, of the brain regions known to be injured with this model. No HSP72-LI was observed in sham-treated controls or flurothyl-treated animals whose seizures were controlled with pentobarbital. HSP72-LI thus localizes to certain regions of seizure-induced injury, and may provide a sensitive method of detecting neuronal 'stress' or injury relatively soon after status epilepticus. Whether or not HSP72 synthesis plays a protective role in the pathogenesis of seizures, or is only a marker for cell injury, remains to be determined.

Animals↗
PubMed1990

Three hamster species with different scrapie incubation times and neuropathological features encode distinct prion proteins.

Given the critical role of the prion protein (PrP) in the transmission and pathogenesis of experimental scrapie, we investigated the PrP gene and its protein products in three hamster species, Chinese (CHa), Armenian (AHa), and Syrian (SHa), each of which were found to have distinctive scrapie incubation times. Passaging studies demonstrated that the host species, and not the source of scrapie prions, determined the incubation time for each species, and histochemical studies of hamsters with clinical signs of scrapie revealed characteristic patterns of neuropathology. Northern (RNA) analysis showed the size of PrP mRNA from CHa, AHa, and SHa hamsters to be 2.5, 2.4, and 2.1 kilobases, respectively. Immunoblotting demonstrated that the PrP isoforms were of similar size (33 to 35 kilodaltons); however, the monoclonal antibody 13A5 raised against SHa PrP did not react with the CHa or AHa PrP molecules. Comparison of the three predicted amino acid sequences revealed that each is distinct. Furthermore, differences within the PrP open reading frame that uniquely distinguish the three hamster species are within a hydrophilic segment of 11 amino acids that includes polymorphisms linked to scrapie incubation times in inbred mice and an inherited prion disease of humans. Single polymorphisms in this region correlate with the presence or absence of amyloid plaques for a given hamster species or mouse inbred strain. Our findings demonstrate distinctive molecular, pathological, and clinical characteristics of scrapie in three related species and are consistent with the hypothesis that molecular properties of the host PrP play a pivotal role in determining the incubation time and neuropathological features of scrapie.

Animals↗
PubMed1990

Neurologic consequences of cocaine use.

Neurologic consequences of cocaine use frequently present as medical emergencies in the form of stroke, repeated seizures, encephalopathy, acute headache, and unusual transient neurological deficits. The often fatal or disabling neurologic syndromes have only recently been recognized but are now well documented. Cocaine use is a significant cause of stroke in young adults, and the full, long-term ramifications of maternal cocaine use on the fetus will not be known for years to come. Unfortunately, there is not effective treatment other than abstinence, and our understanding of the pathophysiology of cocaine-associated neurologic illness remains limited.

Animals↗
PubMed1989

Cerebral infarctions and transient neurologic deficits associated with acquired immunodeficiency syndrome.

PURPOSE: Little information is available concerning the clinical importance of cerebral infarction in patients with acquired immunodeficiency syndrome (AIDS). The purpose of this retrospective study was two-fold: (1) to determine the frequency and clinical characteristics of cerebral infarction and transient neurologic deficits (TNDs) among patients with AIDS; and (2) to identify specific patient subgroups at risk for such complications and whether there were underlying associated diseases requiring specific therapy. PATIENTS AND METHODS: Neurology inpatient and consult service records, neuropathology reports, and the University of California, San Francisco, AIDS computerized registry were used in identifying study cases. Information on demographic background, associated clinical diagnoses, presenting neurologic symptoms and signs, laboratory results, pathologic findings, and clinical follow-up was obtained from each patient's medical record. RESULTS: Twenty-five patients with AIDS (mean age, 38) having clinical or pathologic findings suggestive of focal cerebral ischemia or infarction were identified. Ten patients had non-hemorrhagic cerebral infarctions, 13 had acute TNDs, and two had both. Cerebral infarction was associated with central nervous system (CNS) infections (cryptococcus, four; tuberculosis, one; zoster vasculitis, one) and cardiogenic embolism (one). TNDs were associated with toxoplasmosis (four), cerebral infarction (two), cryptococcal meningitis (one), vasculitis (one), and CNS Kaposi's sarcoma (one). A presumptive cause was absent in five cases of cerebral infarction and eight of TND. All five patients with pathologically proven macroscopic cerebral infarcts were diagnosed clinically before death. CONCLUSIONS: We conclude the following: (1) AIDS patients, especially given their young age, appear to be increased risk for cerebral infarction and TND. (2) Cerebral infarction and TND may be the initial presentation of AIDS. (3) TND and cerebral infarction often signify treatable CNS infection among AIDS patients. (4) The causes of AIDS-related cerebral infarction and TND are unknown in many cases.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures.

PURPOSE: Despite conflicting experimental and clinical evidence, diphenylhydantoin continues to be used for the treatment of alcohol withdrawal seizures in emergency departments and alcohol detoxification centers. Our goal was to evaluate the effectiveness of intravenous diphenylhydantoin for prevention of alcohol withdrawal seizures in high-risk patients using a prospective, randomized, double-blind, placebo-controlled study design. PATIENTS AND METHODS: Ninety alcoholic patients, enrolled within six hours of the initial alcohol-related seizure in a withdrawal episode, were randomly assigned to treatment with intravenous diphenylhydantoin (1,000 mg) or placebo. Seventy-one patients had a history of seizures during prior alcohol withdrawal episodes. Patients with a history of seizures unrelated to alcohol withdrawal were excluded. Drugs known to affect the seizure threshold or demonstrating cross-tolerance with alcohol were withheld. For each patient, the study endpoint was either (1) seizure recurrence or (2) a minimum 12-hour seizure-free observation period after completion of the study drug infusion. RESULTS: During the postinfusion observation period, six of 45 diphenylhydantoin-treated patients and six of 45 placebo-treated patients experienced at least one recurrent seizure. Equivalent diphenylhydantoin serum levels were measured in patients with and without subsequent seizures. There was no statistically significant difference between the response rates for the two treatments (p greater than 0.05). The 95% confidence interval for the difference in response probabilities was -14.0%, 14%. CONCLUSION: When administered to non-epileptic patients within six hours of the onset of alcohol withdrawal seizures, intravenous diphenylhydantoin failed to show a significant benefit over placebo in the prevention of subsequent seizures. We suggest that the well-documented risks of intravenous diphenylhydantoin therapy outweigh the potential benefit in the short-term treatment of alcohol withdrawal seizures.

Adult↗
PubMed1989

Controlled trial of botulinum toxin injections in the treatment of spasmodic torticollis.

We administered local injections of botulinum toxin to 20 patients with torticollis in a blinded, placebo-controlled study. Each patient received four sets of injections: three different doses of botulinum toxin and one placebo. The order of the sessions was random and unknown to the patients. Sixteen of the patients (80%) reported subjective improvement to at least one dose of botulinum toxin; 11 (55%) reported substantial improvement. No objective benefit was documented. Side effects were minor and transient, although dysphagia occurred in four. Some patients reported that the effect waned despite persistent relaxation or even flaccidity of previously overactive muscles, suggesting a change in the pattern of muscle activity after botulinum toxin injections.

Adult↗