Showing papers by "Icahn School of Medicine at Mount Sinai published in 2000"

The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains

Abstract: Acommon focus among molecular and cellular biologists is the identification of proteins that interact with each other. Yeast two-hybrid, cDNA expression library screening, and coimmunoprecipitation experiments are powerful methods for identifying novel proteins that bind to one's favorite protein for the purpose of learning more regarding its cellular function. These same techniques, coupled with truncation and mutagenesis experiments, have been used to define the region of interaction between pairs of proteins. One conclusion from this work is that many interactions occur over short regions, often less than 10 amino acids in length within one protein. For example, mapping studies and 3-dimensional analyses of antigen-antibody interactions have revealed that epitopes are typically 4-7 residues long (1). Other examples include protein-interaction modules, such as Src homology (SH) 2 and 3 domains, phosphotyrosine binding domains (PTB), postsynaptic density/disc-large/ZO1 (PDZ) domains, WW domains, Eps15 homology (EH) domains, and 14-3-3 proteins that typically recognize linear regions of 3-9 amino acids. Each of these domains has been the subject of recent reviews published elsewhere (2 3 4 5 6 7). Among the primary structures of many ligands for protein-protein interactions, the amino acid proline is critical. In particular, SH3, WW, and several new protein-interaction domains prefer ligand sequences that are proline-rich. In addition, even though ligands for EH domains and 14-3-3 domains are not proline-rich, they do include a single proline residue. This review highlights the analysis of those protein-protein interactions that involve proline residues, the biochemistry of proline, and current drug discovery efforts based on proline peptidomimetics.-Kay, B. K., Williamson, M. P., Sudol, M. The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains.

Users' Guides to the Medical Literature: XXII: How to Use Articles About Clinical Decision Rules

Abstract: Clinical experience provides clinicians with an intuitive sense of which findings on history, physical examination, and investigation are critical in making an accurate diagnosis, or an accurate assessment of a patient’s fate. A clinical decision rule (CDR) is a clinical tool that quantifies the individual contributions that various components of the history, physical examination, and basic laboratory results make toward the diagnosis, prognosis, or likely response to treatment in a patient. Clinical decision rules attempt to formally test, simplify, and increase the accuracy of clinicians’ diagnostic and prognostic assessments. Existing CDRs guide clinicians, establish pretest probability, provide screening tests for common problems, and estimate risk. Three steps are involved in the development and testing of a CDR: creation of the rule, testing or validating the rule, and assessing the impact of the rule on clinical behavior. Clinicians evaluating CDRs for possible clinical use should assess the following components: the method of derivation; the validation of the CDR to ensure that its repeated use leads to the same results; and its predictive power. We consider CDRs that have been validated in a new clinical setting to be level 1 CDRs and most appropriate for implementation. Level 1 CDRs have the potential to inform clinical judgment, to change clinical behavior, and to reduce unnecessary costs, while maintaining quality of care and patient satisfaction. JAMA. 2000;284:79-84 www.jama.com

Intraneuronal Aβ42 Accumulation in Human Brain

Abstract: Alzheimer's disease (AD) is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SPs are composed of aggregated β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 staining was demonstrated within cultured neurons by confocal immunofluorescence microscopy and within neurons of PS1 mutant transgenic mice. A central question about the role of Aβ in disease concerns whether extracellular Aβ deposition or intracellular Aβ accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate γ-cleaved Aβ42 and suggest that this intraneuronal Aβ42 immunoreactivity appears to precede both NFT and Aβ plaque deposition. This study suggests that intracellular Aβ42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Aβ42 aggregation may be an important therapeutic direction for the treatment of AD.

Primary care outcomes in patients treated by nurse practitioners or physicians: a randomized trial.

Abstract: ContextStudies have suggested that the quality of primary care delivered by nurse practitioners is equal to that of physicians. However, these studies did not measure nurse practitioner practices that had the same degree of independence as the comparison physician practices, nor did previous studies provide direct comparison of outcomes for patients with nurse practitioner or physician providers.ObjectiveTo compare outcomes for patients randomly assigned to nurse practitioners or physicians for primary care follow-up and ongoing care after an emergency department or urgent care visit.DesignRandomized trial conducted between August 1995 and October 1997, with patient interviews at 6 months after initial appointment and health services utilization data recorded at 6 months and 1 year after initial appointment.SettingFour community-based primary care clinics (17 physicians) and 1 primary care clinic (7 nurse practitioners) at an urban academic medical center.PatientsOf 3397 adults originally screened, 1316 patients (mean age, 45.9 years; 76.8% female; 90.3% Hispanic) who had no regular source of care and kept their initial primary care appointment were enrolled and randomized with either a nurse practitioner (n = 806) or physician (n = 510).Main Outcome MeasuresPatient satisfaction after initial appointment (based on 15-item questionnaire); health status (Medical Outcomes Study Short-Form 36), satisfaction, and physiologic test results 6 months later; and service utilization (obtained from computer records) for 1 year after initial appointment, compared by type of provider.ResultsNo significant differences were found in patients' health status (nurse practitioners vs physicians) at 6 months (P = .92). Physiologic test results for patients with diabetes (P = .82) or asthma (P = .77) were not different. For patients with hypertension, the diastolic value was statistically significantly lower for nurse practitioner patients (82 vs 85 mm Hg; P = .04). No significant differences were found in health services utilization after either 6 months or 1 year. There were no differences in satisfaction ratings following the initial appointment (P = .88 for overall satisfaction). Satisfaction ratings at 6 months differed for 1 of 4 dimensions measured (provider attributes), with physicians rated higher (4.2 vs 4.1 on a scale where 5 = excellent; P = .05).ConclusionsIn an ambulatory care situation in which patients were randomly assigned to either nurse practitioners or physicians, and where nurse practitioners had the same authority, responsibilities, productivity and administrative requirements, and patient population as primary care physicians, patients' outcomes were comparable.

Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis.

Abstract: E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell–cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin–mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin–expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin–expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin–expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin–expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin–expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin–expressing cells.

Recommendations for the establishment of primary stroke centers

Abstract: ObjectiveTo develop recommendations for the establishment and operation of primary stroke centers as an approach to improve the medical care of patients with stroke.ParticipantsMembers of the Brain Attack Coalition (BAC), a multidisciplinary group of representatives from major professional organizations involved with delivering stroke care. Supplemental input was obtained from other experts involved in acute stroke care.EvidenceA review of literature published from 1966 to March 2000 was performed using MEDLINE. More than 600 English-language articles that had evidence from randomized clinical trials, meta-analyses, care guidelines, or other appropriate methods supporting specific care recommendations for patients with acute stroke that could be incorporated into a stroke center model were selected.Consensus ProcessArticles were reviewed initially by 1 author (M.J.A.). Members of the BAC reviewed each recommendation in the context of current practice parameters, with special attention to improving the delivery of care to patients with acute stroke, cost-effectiveness, and logistical issues related to the establishment of primary stroke centers. Consensus was reached among all BAC participants before an element was added to the list of recommendations.ConclusionsRandomized clinical trials and observational studies suggest that several elements of a stroke center would improve patient care and outcomes. Key elements of primary stroke centers include acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. Important support services include availability and interpretation of computed tomography scans 24 hours everyday and rapid laboratory testing. Administrative support, strong leadership, and continuing education are also important elements for stroke centers. Adoption of these recommendations may increase the use of appropriate diagnostic and therapeutic modalities and reduce peristroke complications. The establishment of primary stroke centers has the potential to improve the care of patients with stroke.

Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo.

Abstract: As a result of fatigue, bone sustains microdamage, which is then repaired by bone-remodeling processes. How osteoclastic activity is targeted at the removal of microdamaged regions of bone matrix is unknown. In the current studies, we tested the hypothesis that changes in osteocyte integrity, through the initiation of regulated cell death (apoptosis), are associated with fatigue-related microdamage and bone resorption. Ulnae of adult rats were fatigue-loaded to produce a known degree of matrix damage. Osteocyte integrity was then assessed histomorphometrically from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labeling (TUNEL)-stained sections to detect cells undergoing DNA fragmentation associated with apoptosis; toluidine blue-stained sections were used for secondary morphological confirmation. Ten days after loading, large numbers of TUNEL-positive osteocytes were found in bone surrounding microcracks and in bone surrounding intracortical resorption spaces (approximately 300% increases over controls, p < 0.005). TUNEL labeling in loaded ulnae at sites distant from microcracks or resorption foci did not differ from that in control bone. Osteocytes in toluidine blue-stained sections showed equivalent trends to TUNEL-stained sections, with significant increases in pyknotic nuclei and empty lacunae associated with microcracks and intracortical resorption spaces. TUNEL-positive osteocytes were observed around bone microdamage by 1 day after loading (p < 0.01 relative to baseline), and their number remained elevated throughout the entire experimental period. Increases in empty lacunae and decreases in normal osteocyte numbers were observed over time as well. These studies show that (1) osteocyte apoptosis is induced by bone fatigue, (2) this apoptosis is localized to regions of bone that contain microcracks, and (3) osteoclastic resorption after fatigue also coincides with regions of osteocyte apoptosis. The strong associations between microdamage, osteocyte apoptosis, and subsequent bone remodeling support the hypothesis that osteocyte apoptosis provides a key part of the activation or signaling mechanisms by which osteoclasts target bone for removal after fatigue-induced matrix injury.

Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza A Virus NS1 Protein

Abstract: We present a novel mechanism by which viruses may inhibit the alpha/beta interferon (IFN-alpha/beta) cascade. The double-stranded RNA (dsRNA) binding protein NS1 of influenza virus is shown to prevent the potent antiviral interferon response by inhibiting the activation of interferon regulatory factor 3 (IRF-3), a key regulator of IFN-alpha/beta gene expression. IRF-3 activation and, as a consequence, IFN-beta mRNA induction are inhibited in wild-type (PR8) influenza virus-infected cells but not in cells infected with an isogenic virus lacking the NS1 gene (delNS1 virus). Furthermore, NS1 is shown to be a general inhibitor of the interferon signaling pathway. Inhibition of IRF-3 activation can be achieved by the expression of wild-type NS1 in trans, not only in delNS1 virus-infected cells but also in cells infected with a heterologous RNA virus (Newcastle disease virus). We propose that inhibition of IRF-3 activation by a dsRNA binding protein significantly contributes to the virulence of influenza A viruses and possibly to that of other viruses.

Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy.

Abstract: The time at which ovarian failure (menopause) occurs in females is determined by the size of the oocyte reserve provided at birth, as well as by the rate at which this endowment is depleted throughout post-natal life. Here we show that disruption of the gene for acid sphingomyelinase in female mice suppressed the normal apoptotic deletion of fetal oocytes, leading to neonatal ovarian hyperplasia. Ex vivo, oocytes lacking the gene for acid sphingomyelinase or wild-type oocytes treated with sphingosine-1-phosphate resisted developmental apoptosis and apoptosis induced by anti-cancer therapy, confirming cell autonomy of the death defect. Moreover, radiation-induced oocyte loss in adult wild-type female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with sphingosine-1-phosphate. Thus, the sphingomyelin pathway regulates developmental death of oocytes, and sphingosine-1-phosphate provides a new approach to preserve ovarian function in vivo.

Influenza A Virus NS1 Protein Prevents Activation of NF-κB and Induction of Alpha/Beta Interferon

Abstract: The alpha/beta interferon (IFN-α/β) system represents one of the first lines of defense against virus infections. As a result, most viruses encode IFN antagonistic factors which enhance viral replication in their hosts. We have previously shown that a recombinant influenza A virus lacking the NS1 gene (delNS1) only replicates efficiently in IFN-α/β-deficient systems. Consistent with this observation, we found that infection of tissue culture cells with delNS1 virus, but not with wild-type influenza A virus, induced high levels of mRNA synthesis from IFN-α/β genes, including IFN-β. It is known that transactivation of the IFN-β promoter depends on NF-κB and several other transcription factors. Interestingly, cells infected with delNS1 virus showed high levels of NF-κB activation compared with those infected with wild-type virus. Expression of dominant-negative inhibitors of the NF-κB pathway during delNS1 virus infection prevented the transactivation of the IFN-β promoter, demonstrating a functional link between NF-κB activation and IFN-α/β synthesis in delNS1 virus-infected cells. Moreover, expression of the NS1 protein prevented virus- and/or double-stranded RNA (dsRNA)-mediated activation of the NF-κB pathway and of IFN-β synthesis. This inhibitory property of the NS1 protein of influenza A virus was dependent on its ability to bind dsRNA, supporting a model in which binding of NS1 to dsRNA generated during influenza virus infection prevents the activation of the IFN system. NS1-mediated inhibition of the NF-κB pathway may thus play a key role in the pathogenesis of influenza A virus.

Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging

Abstract: Background—High-resolution MRI has the potential to noninvasively image the human coronary artery wall and define the degree and nature of coronary artery disease. Coronary artery imaging by MR has been limited by artifacts related to blood flow and motion and by low spatial resolution. Methods and Results—We used a noninvasive black-blood (BB) MRI (BB-MR) method, free of motion and blood-flow artifacts, for high-resolution (down to 0.46 mm in-plane resolution and 3-mm slice thickness) imaging of the coronary artery lumen and wall. In vivo BB-MR of both normal and atherosclerotic human coronary arteries was performed in 13 subjects: 8 normal subjects and 5 patients with coronary artery disease. The average coronary wall thickness for each cross-sectional image was 0.7560.17 mm (range, 0.55 to 1.0 mm) in the normal subjects. MR images of coronary arteries in patients with $40% stenosis as assessed by x-ray angiography showed localized wall thickness of 4.3860.71 mm (range, 3.30 to 5.73 mm). The difference in maximum wall thickness between the normal subjects and patients was statistically significant ( P,0.0001). Conclusions—In vivo high-spatial-resolution BB-MR provides a unique new method to noninvasively image and assess the morphological features of human coronary arteries. This may allow the identification of atherosclerotic disease before it is symptomatic. Further studies are necessary to identify the different plaque components and to assess lesions in asymptomatic patients and their outcomes. (Circulation. 2000;102:506-510.)

A Comparison of Colonoscopy and Double-Contrast Barium Enema for Surveillance after Polypectomy

Abstract: Background After patients have undergone colonoscopic polypectomy, it is uncertain whether colonoscopic examination or a barium enema is the better method of surveillance. Methods As part of the National Polyp Study, we offered colonoscopic examination and double-contrast barium enema for surveillance to patients with newly diagnosed adenomatous polyps. Although barium enema was performed first, the endoscopist did not know the results. Results A total of 973 patients underwent one or more colonoscopic examinations for surveillance. In the case of 580 of these patients, we performed 862 paired colonoscopic examinations and barium-enema examinations that met the requirements of the protocol. The findings on barium enema were positive in 222 (26 percent) of the paired examinations, including 94 of the 242 colonoscopic examinations in which one or more adenomas were detected (rate of detection of adenomas, 39 percent; 95 percent confidence interval, 33 to 45 percent). The proportion of examinations in which ...

The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease.

Abstract: Background The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. Methods Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. Results Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2.3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. Conclusions The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

The Ebola virus VP35 protein functions as a type I IFN antagonist.

Abstract: An assay has been developed that allows the identification of molecules that function as type I IFN antagonists. Using this assay, we have identified an Ebola virus-encoded inhibitor of the type I IFN response, the Ebola virus VP35 protein. The assay relies on the properties of an influenza virus mutant, influenza delNS1 virus, which lacks the NS1 ORF and, therefore, does not produce the NS1 protein. When cells are infected with influenza delNS1 virus, large amounts of type I IFN are produced. As a consequence, influenza delNS1 virus replicates poorly. However, high-efficiency transient transfection of a plasmid encoding a protein that interferes with type I IFN-induced antiviral functions, such as the influenza A virus NS1 protein or the herpes simplex virus protein ICP34.5, rescues growth of influenza delNS1 virus. When plasmids expressing individual Ebola virus proteins were transfected into Madin Darby canine kidney cells, the Ebola virus VP35 protein enhanced influenza delNS1 virus growth more than 100-fold. VP35 subsequently was shown to block double-stranded RNA- and virus-mediated induction of an IFN-stimulated response element reporter gene and to block double-stranded RNA- and virus-mediated induction of the IFN-beta promoter. The Ebola virus VP35 therefore is likely to inhibit induction of type I IFN in Ebola virus-infected cells and may be an important determinant of Ebola virus virulence in vivo.

A meta-analysis of hypnotically induced analgesia: How effective is hypnosis?

Abstract: Over the past two decades, hypnoanalgesia has been widely studied; however, no systematic attempts have been made to determine the average size of hypnoanalgesic effects or establish the generalizability of these effects from the laboratory to the clinic. This study examines the effectiveness of hypnosis in pain management, compares studies that evaluated hypnotic pain reduction in healthy volunteers vs. those using patient samples, compares hypnoanalgesic effects and participants' hypnotic suggestibility, and determines the effectiveness of hypnotic suggestion for pain relief relative to other nonhypnotic psychological interventions. Meta-analysis of 18 studies revealed a moderate to large hypnoanalgesic effect, supporting the efficacy of hypnotic techniques for pain management. The results also indicated that hypnotic suggestion was equally effective in reducing both clinical and experimental pain. The overall results suggest broader application of hypnoanalgesic techniques with pain patients.

“We Don't Carry That” — Failure of Pharmacies in Predominantly Nonwhite Neighborhoods to Stock Opioid Analgesics

Abstract: Background We have observed that many black and Hispanic patients receiving palliative care at a major urban teaching hospital are unable to obtain prescribed opioids from their neighborhood pharmacies. In this study, we investigated the availability of commonly prescribed opioids in New York City pharmacies. Methods We surveyed a randomly selected sample of 30 percent of New York City pharmacies to obtain information about their stock of opioids. For each pharmacy, U.S. Census estimates for 1997 were used to determine the racial and ethnic composition of the neighborhood (defined as the area within a 0.4-km [0.25-mile] radius of the pharmacy) and the proportion of residents who were more than 65 years old. Data on robberies, burglaries, and arrests involving illicit drugs in 1997 were obtained for the precinct in which each pharmacy was located. We used a generalized linear model to examine the relation between the racial or ethnic composition of neighborhoods and the opioid supplies of pharmacies, while...

P-Selectin Glycoprotein Ligand 1 (Psgl-1) Is Expressed on Platelets and Can Mediate Platelet–Endothelial Interactions in Vivo

Abstract: The platelet plays a pivotal role in maintaining vascular integrity. In a manner similar to leukocytes, platelets interact with selectins expressed on activated endothelium. P-selectin glycoprotein ligand 1 (PSGL-1) is the main P-selectin ligand expressed on leukocytes. Searching for platelet ligand(s), we used a P-selectin–immunoglobulin G (IgG) chimera to affinity purify surface-biotinylated proteins from platelet lysates. P-selectin–bound ligands were eluted with ethylenediaminetetraacetic acid. An ∼210-kD biotinylated protein was isolated from both human neutrophil and platelet preparations. A band of the same size was also immunopurified from human platelets using a monoclonal anti–human PSGL-1 antibody and could be blotted with P-selectin–IgG. Under reducing conditions, both the predicted PSGL-1 ∼210-kD dimer and the ∼120-kD monomer were isolated from platelets. Comparative immunoelectron microscopy and Western blotting experiments suggested that platelet PSGL-1 expression is 25–100-fold lower than that of leukocytes. However, patients with chronic idiopathic thrombocytopenic purpura who harbor predominantly young platelets displayed greater expression, indicating that PSGL-1 expression may be decreased during platelet aging. By flow cytometry, thrombin-activated platelets from normal individuals exhibited greater expression than those unstimulated. An inhibitory anti–PSGL-1 antibody significantly reduced platelet rolling in mesenteric venules, as observed by intravital microscopy. Our results indicate that functional PSGL-1 is expressed on platelets, and suggest an additional mechanism by which selectins and their ligands participate in inflammatory and/or hemostatic responses.

A randomized controlled trial of prednisone in Alzheimer’s disease

Abstract: To the Editor: We read with interest the article by Aisen et al.,1 who found that low doses of prednisone are not effective in AD. In the article, inflammatory processes are discussed in the pathophysiology of dementia, and corresponding therapeutic approaches are pursued. However, no clear clinical evidence for this exciting hypothesis has been established yet. To acquire information about the inflammatory activity of patients with expected dementia transferred to our ward, we investigated eosinophilic cationic protein (ECP) in serum. ECP is a sensitive marker of inflammatory processes and often used as a marker in clinical studies.2 We have 41 patients (mean age 73.8 years, SD 7.8; 7 men, 34 women) in our study. …

Limbic Circuitry in Patients With Autism Spectrum Disorders Studied With Positron Emission Tomography and Magnetic Resonance Imaging

Abstract: OBJECTIVE: Cytoarchitectonic changes in the anterior cingulate cortex, hippocampus, subiculum, entorhinal cortex, amygdala, mammillary bodies, and septum were reported in a postmortem study of autism. Previously, the authors found smaller cingulate volume and decreased metabolism of the cingulate in seven autistic patients. In this study, they measured the volume and glucose metabolism of the amygdala, hippocampus, and cingulate gyrus in an expanded group of 17 patients with autism spectrum disorders (autism [N=10] or Asperger’s disorder [N=7]) and 17 age- and sex-matched healthy volunteers. METHOD: Subjects performed a serial verbal learning test during 18F-deoxyglucose uptake. The amygdala, hippocampus, and cingulate gyrus were outlined on magnetic resonance imaging scans, volumes of the structures were applied to matching coregistered positron emission tomography scans, and three-dimensional significance probability mapping was performed. RESULTS: Significant metabolic reductions in both the anterior a...

Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats.

Abstract: The present study examined the long-standing concept that changes in hippocampal circuitry contribute to age-related learning impairment. Individual differences in spatial learning were documented in young and aged Long-Evans rats by using a hippocampal-dependent version of the Morris water maze. Postmortem analysis used a confocal laser-scanning microscopy method to quantify changes in immunofluorescence staining for the presynaptic vesicle glycoprotein, synaptophysin (SYN), in the principal relays of hippocampal circuitry. Comparisons based on chronological age alone failed to reveal a reliable difference in the intensity of SYN staining in any region that was examined. In contrast, aged subjects with spatial learning deficits displayed significant reductions in SYN immunoreactivity in CA3 lacunosum-moleculare (LM) relative to either young controls or age-matched rats with preserved learning. SYN intensity values for the latter groups were indistinguishable. In addition, individual differences in spatial learning capacity among the aged rats correlated with levels of SYN staining selectively in three regions: outer and middle portions of the dentate gyrus molecular layer and CA3-LM. The cross-sectional area of SYN labeling, by comparison, was not reliably affected in relation cognitive status. These findings are the first to demonstrate that a circuit-specific pattern of variability in the connectional organization of the hippocampus is coupled to individual differences in the cognitive outcome of normal aging. The regional specificity of these effects suggests that a decline in the fidelity of input to the hippocampus from the entorhinal cortex may play a critical role.

Survival in End-Stage Dementia Following Acute Illness

Abstract: ContextLittle is known about the prognosis of acutely ill patients with end-stage dementia or about the type of care that these patients receive. If their prognosis is poor, then emphasis should be placed on palliative care for these patients rather than on curative interventions.ObjectivesTo examine survival for patients with end-stage dementia following hospitalization for hip fracture or pneumonia and to compare their care with that of cognitively intact older adults.DesignProspective cohort study with 6 months of follow-up.Setting and PatientsPatients aged 70 years or older who were hospitalized with hip fracture (cognitively intact, n=59; with end-stage dementia, n=38) or pneumonia (cognitively intact, n=39; with end-stage dementia, n=80) in a large hospital in New York, NY, between September 1, 1996, and March 1, 1998.Main Outcome MeasuresMortality, treatments directed at symptoms, and application of distressing and painful procedures in cognitively intact patients vs those with end-stage dementia.ResultsSix-month mortality for patients with end-stage dementia and pneumonia was 53% (95% confidence interval [CI], 41%-64%) compared with 13% (95% CI, 4%-27%) for cognitively intact patients (adjusted hazard ratio, 4.6; 95% CI, 1.8-11.8). Six-month mortality for patients with end-stage dementia and hip fracture was 55% (95% CI, 42%-75%) compared with 12% (95% CI, 5%-24%) for cognitively intact patients (adjusted hazard ratio, 5.8; 95% CI, 1.7-20.4). Patients with end-stage dementia received as many burdensome procedures as cognitively intact patients and only 8 (7%) of 118 patients with end-stage dementia had a documented decision made to forego a life-sustaining treatment other than cardiopulmonary resuscitation. Only 24% of patients with end-stage dementia and hip fracture received a standing order for analgesics.ConclusionsIn this study, patients with advanced dementia and hip fracture or pneumonia had a very poor prognosis. Given the limited life expectancy of patients with end-stage dementia following these illnesses and the burdens associated with their treatment, increased attention should be focused on efforts to enhance comfort in this patient population.