Cholinergic mechanisms and cognitive decline.
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Biomedical subjects
Publications and source records attributed to E Perry.
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Autologous transplantation using bone marrow stem cells (BMSC) or peripheral blood stem cells (PBSC) is widely used for non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). We report a randomized, comparative trial comparing BMSC vs. non-mobilized PBSC for responsive NHL or HD. Patients randomized to BMSC (n = 13) vs. PBSC (n = 15) had more rapid neutrophil recovery (median 23 vs. 30 days), RBC independence (25 vs. 62 days), platelet independence (24 vs. 54 days), and shorter hospital stay. However, neither relapse, overall survival, nor relapse-free survival were different receiving BMSC vs. PBSC (all P > .7). Concurrently, 54 others (34 BMSC, 20 PBSC) were assigned non-randomly because of resistant disease or marrow unsuitable for harvest and similar patterns of engraftment favoring BMSC over PBSC were observed. In the entire group, BMSC transplantation (n = 47) led to quicker neutrophil recovery (P = .02), RBC (P = .06), and platelet independence (P =.04) and earlier hospital discharge (P = .02) vs. PBSC (n = 35). No difference in relapse, overall, or relapse-free survival were observed using BMSC vs. PBSC. These data suggest that non-mobilized PBSC are a satisfactory alternative to BMSC in patients with unsuitable marrow; however, transplantation with non-mobilized PBSC was associated with slower hematologic recovery, and longer hospital stay. No difference in tumor recurrence rates was observed between the PBSC or BMSC recipients. Unprimed PBSC transplantation offered no clinical advantage to BMSC.
Senile dementia of Lewy body type or Lewy body dementia (SDLT or LBD) is defined as a Lewy body associated disease presenting in the elderly primarily with dementia with variable extrapyramidal disorder. Characteristic clinical symptoms include fluctuating cognitive impairment, psychotic features such as hallucinations and a particular sensitivity to neuroleptic medication. Although apolipoprotein e4 allele is increased 2-3 fold in SDLT (as in Alzheimer's disease) and beta-amyloidosis occurs in most cases, the most robust neurobiological correlate of the dementia so far identified appears to be extensive cholinergic deficits in the neocortex. This is consistent with previously reported correlations between cortical cholinergic activity and dementia in Parkinson's disease (PD) and Alzheimer's disease. There is also a significant interaction between the density of limbic cortical Lewy bodies and dementia in both SDLT and PD, although the cortical neuronal population affected remains to be identified. Cortical Lewy body density is positively correlated with the age of disease onset in PD and SDLT. This may account for the increased incidence of psychiatric syndromes, as opposed to extrapyramidal disorder in Lewy body disease with advancing age as may age-related loss of cholinergic activity in cortical areas such as the hippocampus.
The current case describes a young woman with diabetes mellitus who developed end-stage renal disease (ESRD) and many other devastating complications related to her primary illness. Her experience illustrates many ways in which complicated illness can interrupt life's plans, dashing any dreams that she or her family might have for the future. Yet her story also illustrates the important role that a trained Peer Resource Consultant (PRC) can play in helping to better understand chronic illness, face and grieve losses, and even design new plans and create new dreams for the future. The discussion that follows includes several perspectives that offer poignant insight into the difficult situations characterized by the young diabetic with ESRD.
The aetiology of the common dementias of old age remains incompletely understood. Here we describe some of the biological, neurophysiological and psychological changes associated with ageing of the human brain, in terms of those that occur throughout life and those that are characteristic of senescence. Age-dependent diseases, such as Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD) and dementia with Lewy bodies (DLB), are considered from these viewpoints, and risk factors described. Vascular dementia (VaD) is related to hypertension and atherosclerosis and detailed description of its pathogenesis is outside the scope of this review. The importance of age as the main risk factor raises basic questions about the relationship of these diseases to the ageing process itself. Similarities and differences between ageing and disease may be important for a rational approach to prevention and treatment of cognitive decline and dementia in later life.
General experience and reported data show that a substantial number of patients, at least 10% in many surveys, eventually choose to withdraw from chronic dialysis. There are additional studies suggesting that discussing and completing advance directives (AD) can promote more acceptance and less acrimony for patients, families, and staff when patients die. Even so, surprisingly few AD are completed, and dialysis staff often shun discussion of AD with patients. Thus, in this study, a survey of approximately 400 dialysis staff from 12 representative Michigan dialysis facilities was undertaken both to determine the beliefs, attitudes, and life experiences that might influence such discussions, as well as to guide future strategies aimed at encouraging the discussion and meaningful execution of AD. More than 50% (210) of the distributed questionnaires were completed. Overall results show that respondents report having discussed AD with only 30% of patients on average and that as many as 40% of respondents report never having done so. Among the professional disciplines responding to this survey, social workers report the largest percentage of patients with whom they discussed AD (60%), physicians a smaller percentage (38%), licensed practical (30%) and registered (25%) nurses even fewer patients, and dialysis technicians (20%) and dietitians (4%) the least. Across all disciplines, staff reported discussing AD with a larger percentage of patients when staff had experienced significant losses within their own personal lives, discussed such issues with friends or family, or had prepared their own AD. In rating specific barriers that correlated strongly with reported discussion of AD, each professional discipline had characteristic responses reflecting the approach of the discipline to addressing AD. The survey results suggest that the interdisciplinary variations observed are attributable to: (1) important differences not only in training, but also in the customary roles taken by each discipline; (2) inherent cultural differences, suggested by the findings among nonwhite staff of a lower reported frequency of having discussed AD with patients and of more concern over the barriers to doing so; and (3) a lack of support from supervisory and physician staff within the dialysis team. In conclusion, this survey shows, not surprisingly, that personal experiences and intrinsic cultural differences influence the attitudes of dialysis staff toward discussing AD with patients. The results of this survey underscore important differences between individual professional disciplines that affect both the perceived barriers to, as well as the likelihood of, discussing AD with patients. It seems that emotional issues such as death and dying stress interdisciplinary team interaction and amplify discomfort. However, it may be possible to increase the level of comfort in talking to patients about AD for each professional discipline by addressing the findings from this study (role differences and barriers) through focused interventions and by facilitating mutual support among the distinct members of the dialysis staff.
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Patients on chronic dialysis were surveyed to determine the degree to which completion of advance directives (ADs) was influenced by personal factors that patients bring to their dialysis situation (eg, demographic characteristics or personal preferences) and by environmental factors that are not under their control (eg, interaction with dialysis staff or hospital system). Of the 113 questionnaires distributed to the population of 40 hemodialysis and 73 peritoneal dialysis patients, 90 (80%) were completed. Although only 17% of the respondents had actually completed written ADs previously, respondents seemed to have a good general understanding of ADs, as evidenced by the 80% overall accuracy on a 19-question portion of the survey that tested knowledge regarding ADs. While a few personal factors, such as gender, dialysis, modality, perceived quality of life, and attitude toward death, were associated with completion of ADs, most other demographic variables, including age, marital status, religion, work status, number of years of education, disability status, locus of control, renal diagnosis, and number of years on dialysis, were not correlated. More prominently correlated with completion of ADs were environmental factors, such as having dialysis staff discuss ADs with patients, patients being asked to complete ADs at the time of hospitalization, and perception of staff as being comfortable discussing ADs with patients. The overall results of the survey suggest that discussing ADs as an ongoing activity may have been positively influenced by the Federal Patient Self-Determination Act of 1991.(ABSTRACT TRUNCATED AT 250 WORDS)
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Neuronal nicotinic acetylcholine receptors consist of different subunits, alpha and beta, with different subtype arrangement corresponding to distinct pharmacological and functional properties. The expression of alpha 3, alpha 7 and beta 2 mRNA in the human brain was studied by in situ hybridization and compared to [3H]nicotine, [3H]cytisine and [125I]alpha-bungarotoxin binding in contiguous sections. The beta 2 probe showed a strong hybridization signal in the granular layer of the dentate gyrus and in the CA2/CA3 region of the hippocampus and in the insular cortex, and a signal of lower intensity in the subicular complex and entorhinal cortex. The alpha 3 probe showed strong hybridization in the dorsomedial, lateral posterior, ventroposteromedial and reticular nuclei of the thalamus, and a weak signal in the hippocampal region and in the entorhinal, insular and cingular cortex. The amount of alpha 7 mRNA was high at the level of the dentate granular layer and the CA2/CA3 region of the hippocampus, in the caudate nucleus and in the pulvinar and ventroposterolateral nuclei of the thalamus. [3H]Nicotine and [3H]cytisine binding appeared to be identical in anatomical distribution and relative intensity. It was high in the thalamic nuclei, the putamen and in the hippocampal formation in the subicular complex and the stratum lacunosum moleculare. The level of [125I]alpha-bungarotoxin binding was particularly high in the hippocampus and in the pyramidal cells of the CA1 region, but was relatively low in the subicular complex. Our data indicate that in the human brain nicotinic receptor subtypes have discrete distributions, which are in part different from those of other species.
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Neuronal nicotinic acetylcholine receptors (nAchRs) are multimeric proteins constituted of two different subunits, alpha and beta, with different subtypes arrangement and different pharmacological and functional properties. nAchRs mediate neurotransmission in many central and peripheral synapses and appear to be affected in human degenerative disorders. We have studied the distribution of nAchR in human brain, particularly in the hippocampus and thalamus, by binding of 3H-nicotine and 3H-cytisine and by in situ hybridization with human alpha 3 and beta 2 nAchR subunits of mRNA. An alpha 3 probe shows a strong hybridization signal in the thalamus, while a beta 2 probe has a good signal at the level of the enthorinal cortex, hippocampus and in caudate and putamen. The alpha 3 and beta 2 mRNA localization is different from that described in other species. 3H-nicotine and 3H-cytisine binding were very similar in terms of anatomical distribution and comparable to the binding described in other animal species. The binding of the two ligands was distributed over the areas labeled by the alpha 3 and beta 2 probes and did not completely overlap with either of the subunits.
This multidisciplinary discussion focuses on the case of a young diabetic woman who chose to stop chronic hemodialysis during a long and complicated illness. The perspective presented here include an academic lawyer's view of such medical decisions; a hospital chaplain's view of the religious framework for end-of-life situations; a clinical psychiatrist's considerations when consulted to evaluate patients in such straits; a transplant nurse's view of the opportunities for personal interaction that such clinical situations present; and a renal social worker's approach to chronic illness, advance directives, and death in the dialysis patient population. The discussion is intended to address objectively some important issues associated with death in this population, aimed at increasing our willingness to discuss these issues more openly with patients and with our colleagues.
We performed three types of studies to evaluate the genotoxicity of the chlorinated organic solvent perchloroethylene (PERC or tetrachloroethylene) and its volatile metabolites, trichloroacetyl chloride (TCAC) and trichloroacetic acid (TCA), as well as the volatile metabolites of trichloroethylene, i.e. dichloroacetyl chloride (DCAC), dichloroacetic acid (DCA), and 2,2,2-trichloroethanol (TCE). In the first set of studies, which involved the evaluation of these chemicals in the Microscreen prophage-induction assay, only DCA (+S9) was genotoxic, producing 6.6-7.2 plaque-forming units/mM. This places DCA among the weakest of the > 100 chemicals that have been identified previously as inducers of prophage in this assay. In the second set of studies, which involved the evaluation of these chemicals in the vapor state in Salmonella TA100 using a Tedlar bag vaporization technique, DCA (+/-S9), DCAC (-S9), and TCAC (+/-S9) were mutagenic, producing 3-5x increases in revertants/plate relative to the background. S9 enhanced the mutagenic potency of DCA but had no effect on the mutagenic potency of TCAC. The potencies ranged from 0.7 to 3.9 rev/p.p.m., resulting in a potency ranking of DCA > DCAC approximately TCAC. The lowest effective concentrations were 50-300 p.p.m., which are similar to those for ethylene oxide and epichlorohydrin in this assay. In the third set of studies, the mutation spectra of DCA, DCAC, and TCAC were determined at the base-substitution allele hisG46 of Salmonella TA100. DCA and DCAC induced primarily G.C-->A.T transitions, whereas TCAC induced primarily G.C-->T.A transversions, which was also the predominant mutation among the background revertants.(ABSTRACT TRUNCATED AT 250 WORDS)
To carry out cord blood transplants from allogeneic unrelated donors, cord blood stem cell banks must be established. This report proposed the policies and procedures that can be used to establish cord blood banks. The areas covered include donor consent and suitability criteria; infectious and genetic disease testing; collection, processing, and preservation of the cord blood; retention of specimens for special testing; confidentiality; documentation and record keeping; establishment of a quality control program; and related regulatory issues. There are no technologic impediments to establishing cord blood banks. Agreement on some standard policies and procedures would facilitate exchange of cord blood stem cells among transplant centers and should increase the number of transplants that can be done.
The effect of prior advance directives (AD) on the outcome when chronic dialysis patients died was evaluated in a retrospective review of consecutive deaths over a period of more than 6 yr in a large academic dialysis center. Among 182 patients who died during the period under review, 74 (41%) had previously stated their AD verbally or in writing and the prevalence of AD was highest among patients with age-related or chronically debilitating diseases. Previous statement of AD was significantly more prevalent (P < 0.001) among patients who withdrew from treatment in reconciled fashion than among patients who died suddenly and unexpectedly or who died without a reconciled decision to forego life-sustaining intervention (e.g., dialysis, intubation, emergency surgery). Further analysis shows that patients stating prior AD and patients withdrawing from treatment were most often those who made their own medical decisions ("internal" locus of decision making), rather than relying on relatives or other agents ("external" locus), and tended to be those with a definite spouse or spouse-equivalent relationship. Finally, retrospective assessment suggests that cases in which patients stated prior AD and cases in which patients withdrew from treatment were associated more frequently with a favorable outcome. It was concluded that addressing AD before a medical crisis ensues may increase the likelihood of a "good death" when complications bring the course of chronic dialysis to termination.(ABSTRACT TRUNCATED AT 250 WORDS)
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