Biomedical subjects
Publications and source records attributed to L A Hansen.
Subsumed under the rubric of Lewy body disease are idiopathic Parkinson's disease (PD), pure diffuse Lewy body disease (DLBD), and, most commonly, combined brainstem and neocortical Lewy bodies with Alzheimer's disease (AD) pathology in a relatively early developmental stage. Clinical correlates are dementia with psychiatric and subcortical features plus mild extrapyramidal signs (EPS).
Changes in medical education towards a student-centered, problem-based learning, with continuity care experience in ambulatory settings have been recommended. The University of South Dakota School of Medicine has developed such an educational model for third year medical students named the Yankton Model Program and is herein described.
Entorhinal cortex is the major source of hippocampal afferents. Its neurons, especially in layer 2, develop neurofibrillary tangles (NFTs) in Alzheimer disease (AD). We quantified entorhinal NFTs in cases of AD, elderly controls, and in brains with both AD pathology and subcortical and neocortical Lewy bodies, (a Lewy body variant, LBV). A nosologic controversy hinges on whether LBVs are a form of AD or a different disease, since they have few neocortical NFTs and their neuritic plaques often lack paired helical filament immunoreactivity. The LBVs had more entorhinal NFTs than controls (P less than 0.001), but fewer than ADs (P less than 0.02), despite comparable numbers of neuritic plaques. AD pathology in LBVs is of moderate severity, or perhaps in an earlier developmental stage.
We studied the neuropathologic effects of chronic alcohol ingestion on the brains of healthy, well-nourished, male mongrel dogs. Five experimental dogs were provided 36% of their calories as ethyl alcohol for 1 year. Following killing, their brains were weighed, photographed, sectioned, and processed for computerized morphometric determinations of ventricular size, cortical thickness, and neocortical neuron and glial cell populations. Compared with a similarly handled control group, the alcoholic dog brains showed lateral ventricular enlargement, cortical thinning in the temporal lobe only, and fewer glial cells in the temporal and frontal cortices. There were no statistically significant differences between the alcoholic and control groups in brain weight, frontal or parietal cortical thickness, or neocortical neuron populations. These results imply a disproportionate vulnerability of white matter to the damaging effects of alcohol with consequent lateral ventricular enlargement, and some regional variation in neocortical susceptibility to alcohol-induced cortical thinning and glial cell loss. In general, such changes are consistent with those described in neuroradiologic imaging studies of human alcoholics.
Most clinically demented elderly patients are found at autopsy to have Alzheimer's disease, multi-infarct dementia, Parkinson's disease, Pick's disease, or Creutzfeldt-Jakob disease. We studied 5 patients clinically characterized by late onset dementia whose brains showed no pathological evidence of Alzheimer's disease, or any other specific neuropathological diagnosis. We found argyrophilic grains, coiled bodies, abundant Alz-50-positive and thioflavine S-negative neurofibrillary tangles, and neuropil threads in the hippocampus, entorhinal cortex, locus ceruleus, substantia nigra, subthalamic nucleus, and inferior olives. Ultrastructurally, the grains, threads, and tangles were composed of straight tubulofilamentous structures, 25 nm in diameter, similar to those found in patients with progressive supranuclear palsy but different from the paired helical filaments of patients with Alzheimer's disease. These findings suggest that the late onset dementia with argyrophilic grains syndrome is also characterized by the presence of tangles and threads with the topographical distribution of progressive supranuclear palsy.
We present here both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of 15 patients with Alzheimer's disease and 9 neuropathologically normal subjects. The statistical data show only weak correlations between psychometric indices and plaques and tangles, but the density of neocortical synapses measured by a new immunocytochemical/densitometric technique reveals very powerful correlations with all three psychological assays. Multivariate analysis by stepwise regression produced a model including midfrontal and inferior parietal synapse density, plus inferior parietal plaque counts with a correlation coefficient of 0.96 for Mattis's Dementia Rating Scale. Plaque density contributed only 26% of that strength.
The benefits of two dosing methods, patient-controlled analgesia (PCA) with morphine sulfate (MS) alone and PCA plus continuous infusion of morphine sulfate (PCA + CI) were clinically evaluated in a randomized, single-blinded study of 30 adult abdominal surgery patients. Doses were adjusted based on pain and sedation ratings. Respirations, pulse, blood pressure, pain and sedation ratings were assessed. Subjects rated their pain twice daily using a visual analog scale for 72 hr postoperatively. The subjects reported pain relief with both dosing regimens. No statistically significant differences between the groups were found in pain and sedation ratings, or length of time using the device, with the exception of a higher amount of MS used on postoperative day two by the infusion group (p less than 0.003). There seems to be a trend for the PCA + CI group to have less fluctuation in sedation between days and better pain control (as demonstrated by verbal and visual analog pain scores) on the third postoperative day. Statistical significance was not found, however. PCA plus continuous infusion of MS may be a beneficial approach to the management of postoperative pain in selected patients; studies to identify these patients need to be done.
Altretamine is a National Cancer Institute-designated group C antineoplastic agent used in the treatment of advanced ovarian cancer. Altretamine is a highly lipid-soluble drug available only for oral administration as a capsule. The drug is activated through metabolic oxidation to intermediate methylol derivatives and formaldehyde. It is unclear which metabolite is the major species responsible for cytotoxicity or the primary mechanism of cytotoxicity. As a single agent in the treatment of ovarian cancer, altretamine demonstrates a response rate similar to other active agents in this disease (21-39 percent). The major utility of altretamine is in combination with other agents such as cyclophosphamide, doxorubicin, fluorouracil, melphalan, and cisplatin. However, few randomized trials have evaluated the contribution of altretamine in these multiagent combinations. Dose-limiting toxicities include gastrointestinal (nausea, vomiting, anorexia), hematologic, and neurotoxic (peripheral neurotoxicity). The therapeutic role of altretamine is limited because of a toxicity profile similar to that of cisplatin, one of the more active agents in ovarian cancer. Its use should be reserved for patients who are not candidates for more standard platinum-based regimens.
A 65-year-old woman presented with a mild memory impairment, spatial disorientation, and poor task initiation. Progression was rapid over 3 months. She developed severe apathy, delusions, extrapyramidal features, and psychometrically quantified cognitive deterioration. Her brain showed many neocortical neuritic plaques and neurofibrillary tangles along with neocortical and brainstem Lewy bodies and temporal lobe spongiform vacuolization. This case is the most rapid deterioration documented of a patient with Alzheimer's disease and Lewy bodies.
Neuritic (senile) plaques are a hallmark of the pathology found in the brain of patients afflicted with Alzheimer's disease (AD). Neuritic plaques have been considered to be composed of an amyloid core surrounded by dilated neurites, although the use of anti-beta/A4-protein antibody revealed the presence of diffuse plaques without a nuclear-like central mass or surrounding paired helical filament (PHF)-containing neuritic components. The presence of diffuse plaques without PHF-containing neuritic components strongly suggests that the formation of amyloid precedes the degeneration of neurites that surround amyloid. Diffuse plaques are thus considered to be an early marker of AD pathology. In this article, we report that diffuse plaques, possible markers of early AD pathology, are immunostained with anti-protein kinase C(beta II) [anti-PKC(beta II)] antibodies. The PKC(beta II)-immunoreacting components of the diffuse plaques extend from neurons embedded in the plaques. Immunoelectron microscopy of diffuse and mature neuritic plaques shows that PKC(beta II)-like immunoreactivity in the plaques is closely associated with membranous structures of fine neuronal processes apposed to the amyloid fibers. These fine neuronal processes are distinct from classical neurites found typically in mature neuritic plaques. Furthermore, biochemical analysis demonstrates that PKC abnormalities, but not other AD markers (ubiquitin and A68), were found in the neocortex of clinically nondemented individuals with cortical plaques. Therefore, the PKC alteration in neurons might be involved in the early pathophysiology of AD.
The impact of a decision analysis model on pharmacists' preferences for a drug therapy was studied. Three hundred forty members of the American College of Clinical Pharmacy were randomly assigned to receive either a copy of a drug therapy review alone (control group) or the review plus a decision analysis of the same clinical problem (experimental group). The disease selected was pseudomembranous colitis, and the drugs to be considered were vancomycin, metronidazole, and bacitracin. The review and the decision analysis recommended metronidazole as the best agent. Each subject completed a short questionnaire, read the review or the review plus the analysis, and completed a follow-up questionnaire. Both questionnaires asked the subjects to rank the agents in order of preference. There were 164 usable responses, 86 from the control group and 78 from the experimental group; the total response rate was 48.2%. The difference in the proportion of respondents in each group who chose metronidazole as the most preferred agent, both before and after the intervention, was not significant. Of the 40 experimental-group subjects who ranked metronidazole as their second or third choice in the pretest, 16 (40%) ranked it as the most preferred agent in the posttest. Ten of these 16 stated that the model influenced their decision. Decision analysis plus a drug therapy review had no greater impact on pharmacists' opinions on the selection of drug therapy for pseudomembranous colitis than did the review alone. The model did influence some of those who changed their opinion.
Quantification of synaptophysinlike immunoreactivity is a valuable method for studying the presynaptic terminals in the normal and damaged nervous system. The present report shows that in the control brain, the predominant pattern of synaptic immunostaining in the neocortex was that of an evenly distributed densely granular immunolabeling of the neuropil, while in the paleocortex and in subcortical areas of the brain most of the presynaptic terminals were distributed along the dendritic arborizations or around the neuronal somata. The immunochemical and the immunohistochemical analysis of the Alzheimer's disease tissue showed that the frontal and parietal cortex presented the most severe and widespread loss, with a 45% loss in synaptophysin immunoreactivity. These areas showed an average 35% loss of large neurons. The visual cortex, hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus ceruleus displayed some degree of loss, but to a lesser extent. In addition to this loss, the basic patterns of organization of the presynaptic terminals were altered, with the presence of abundant, enlarged synaptophysin-labeled terminals. This study further supports the role of synaptic pathology in Alzheimer's disease.
BACKGROUND: --The purpose of this study is a prospective assessment of morphine sulfate administration by intermittent intravenous (IV) injections (Int-IV) vs patient-controlled analgesia (PCA) in patients in the emergency department (ED) with sickle cell crisis pain. METHODS: --Patients were at bed rest and received intravenous hydration. Linear analog scale for pain intensity and verbal pain scale, level of alertness, and vital signs were assessed prior to therapy, every 60 minutes thereafter, and at the time of discharge from the ED. Patients were randomized to Int-IV or PCA. During phase 1, patients in the Int-IV group received morphine sulfate 4 mg IV every 30 to 60 minutes as necessary for a linear analog scale for pain intensity greater than 50 mm. The patients in the PCA group received morphine sulfate 2 mg bolus then 1.0 mg with a 6-minute lockout. During phase 2, patients in the Int-IV group received morphine sulfate 8 mg IV every 30 to 60 minutes as necessary for a linear analog scale for pain intensity greater than 50 mm. The patients in the PCA group received morphine sulfate 5 mg bolus then 2.7 mg with a 10-minute lockout. Data were analyzed by unpaired t test, general linear modeling, Mann-Whitney U test, and chi 2 test. RESULTS: --During phase 1, 10 patients (28.3 +/- 7.3 years) received Int-IV and 10 patients (33.9 +/- 12.5 years) received PCA. Treatment groups did not differ significantly regarding duration of pain, amount of morphine administered, linear analog scale for pain intensity, verbal pain scale, level of alertness, or vital signs except for a significantly lower final respiratory rate with Int-IV. In phase 2, 12 patients (28.4 +/- 5.6 years) received Int-IV and 13 patients (26.8 +/- 8.1 years) received PCA. The PCA groups had a significantly shorter elapsed time between onset of pain and treatment (7.3 +/- 6.5 hours) when compared with the Int-IV group (18 +/- 16.9 hours). Treatment groups did not differ significantly with respect to total amount of morphine administered, linear analog scale for pain intensity, verbal pain scale, vital signs, or level of alertness. The PCA group had a significant reduction in length of stay in the ED during phase 2 when compared with phase 1. The ED discharge rate and the incidence of side effects did not differ significantly between groups. CONCLUSION: --At both the low- and high-dose regimens, PCA is equally safe and effective and may be used in place of Int-IV administration of morphine in the ED treatment of sickle cell crisis pain.
Alzheimer disease (AD) is characterized, among other pathological alterations, by an extensive synapse loss. Brain spectrin is a membrane skeleton protein found in synapses, and its immunoreactivity has been shown to increase in the rat model of denervation. In order to test the hypothesis that there is an increase in brain spectrin immunoreactivity in relation to the synapse pathology in AD, we studied brain sections and homogenates from AD and control cases and found increased anti-brain spectrin immunostaining of neurons, fibers, and plaques, with a relative decrease in the granular pattern of neuropil immunoreactivity. Western blot analysis showed a 25% increase in the 150 kDa bands (degradation products) in the cytosolic fraction and a decrease in the 240 kDa band (intact brain spectrin) in the particulate fraction. Altered immunostaining of brain sections and Western blot was not observed with an antibody against red blood cell spectrin demonstrating the specific change of brain spectrin. These results support the contention that increased brain spectrin immunoreactivity is a marker of synapse or neuronal loss and further supports the concept of synapse pathology in AD.
A single topical application of 2 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) to CD-1 mouse skin resulted in a rapid decrease in cytosolic, particulate, and total epidermal protein kinase C (PKC) activity at 6 h, which remained decreased by 70% at 96 h. This dose of TPA produced epidermal hyperplasia as determined by an increase in the number of nucleated epidermal cell layers. A single application of 10 mumol sn-1,2-didecanoylglycerol, a model sn-1,2-diacylglycerol and complete tumor promoter, induced ornithine decarboxylase to an extent similar to that of 2 nmol TPA. However, sn-1,2-didecanoylglycerol produced an 80% increase in particulate PKC activity that was accompanied by a 45% decrease in cytosolic PKC activity, resulting in no net change in total PKC activity. Unlike TPA, this dose of sn-1,2-didecanoylglycerol did not produce a hyperplastic response. Additional dosing regimens were examined to determine whether the down-regulation of particulate PKC activity was associated with hyperplasia and tumor promotion. A tumor-promoting dosing regimen consisting of multiple applications of 5 or 10 mumol sn-1,2-didecanoylglycerol twice daily for 1 week resulted in more than a 60% decrease in cytosolic and particulate PKC activity and a marked epidermal hyperplasia. Twice-weekly application of 10 mumol sn-1,2-didecanoylglycerol, a nonpromoting dosing rate, for 1 week decreased cytosolic PKC activity but increased particulate PKC activity and did not produce hyperplasia. Dosing regimens utilizing multiple applications of TPA decreased both particulate and cytosolic PKC activity and were also hyperplastic. PKC activity was also measured in epidermal papillomas from mice initiated with 7,12-dimethylbenz[a]- anthracene and promoted with either sn-1,2-didecanoylglycerol or TPA. Cytosolic- and particulate-associated PKC activity in these papillomas was decreased by at least 70% and 40%, respectively, when compared with epidermis and whole skin. After 2 months without promoter treatment, both cytosolic and particulate PKC activity remained decreased in the papillomas, whereas epidermal PKC activity returned to control values by 2 to 3 weeks following cessation of several weeks of TPA treatment. Collectively, these data demonstrate that the down-regulation of epidermal PKC is associated with and may be a permissive event for epidermal hyperplasia and tumor promotion.
A 62-year-old man presented with memory impairment progressing over 6 years to dementia with near mutism and was diagnosed as having Alzheimer's disease. At autopsy his brain showed lobar atrophy suggestive of Pick's disease and there were spherical intracytoplasmic neuronal inclusions in the fascia dentata, hippocampal pyramidal cell layer, and temporal cortex. Unlike Pick bodies, however, the inclusions were eosinophilic with H&E stains, non-argyrophilic, and failed to react immunohistochemically with antibodies to paired helical filaments or Alz-50. They did label with antibodies to ubiquitin, however, and electron microscopy disclosed dense-cored granular structures with thin filamentous coronas which resembled brain stem-type Lewy bodies. The substantia nigra and locus coeruleus were not affected.
Applying the relatively new technique of laser confocal imaging, vibratome sections which were double immunolabeled for amyloid beta protein and the presynaptic terminal marker synaptophysin were examined. It was found that while synaptic density was generally diminished in Alzheimer's disease (AD) cortical neuropil as compared to controls, the reduction was no greater within the diffuse plaques than outside them. Synapse loss was accentuated, however, within immature and mature plaques. These findings suggest that the pathogenetic process in AD might commence with synapse loss and neurodegeneration rather than with deposition of amyloid beta protein.
Alzheimer disease (AD) as well as other dementing disorders are characterized by a continuous loss of neurons in cortical and subcortical areas and probably by an extensive synaptic loss. In order to substantiate and localize the loss of synapses in AD, we quantified by microdensitometry the neuropil immunoreactivity to an antibody that labels the protein synaptophysin (p38), which is localized in the presynaptic terminals. We found in the AD cases an average 50% decrease in the density of the granular neuropil immunoreaction in parietal, temporal and midfrontal cortex. In contrast, Pick disease cases presented close to normal values in parietal cortex, but major losses in temporal and frontal cortex. Our data strongly suggest an important role of synapse loss in dementia.