Role of Alzheimer's type dementia among dementias of the elderly]

In the authors experience of a memory clinic, about 2/3 of the patients fulfilled the criteria for dementia and among the demented patients 2/3 had probable Alzheimer's disease. Vascular dementia is the second cause of dementia in elderly people, but two other degenerative disorders fulfilling the NINCDS-ADRDA criteria for Alzheimer disease (Mc Khann et al., 1984) account for degenerative dementia. There is now a consensus for the clinical diagnosis and the neuropathological aspects of these two diseases: Dementia with Lewy Bodies (Mc Keith et al., 1996) and fronto-temporal dementia (the Lund and Manchester groups, 1994). The authors emphasize the clinical aspects of those two diseases at an early stage in comparison with dementia of Alzheimer type.     

Clonal disease of natural killer large granular lymphocytes in Taiwan

Lymphoproliferative diseases of large granular lymphocytes (LDGL) may arise from either CD3+ T cells or CD3- natural killer (NK) cells. LDGL with clonal proliferation of large granular lymphocytes (LGL) is defined as LGL leukaemia. The number of patients with NK-LGL leukaemia reported is limited and the pathogenesis of the disease is not yet clear. From 1991 to 1998 six patients with cytogenetically proved clonal disease of NK-LGL were identified in our institute. All were seropositive for Epstein-Barr virus (EBV). EBV RNA or DNA could be detected in LGL from four patients by EBV in situ hybridization or Southern blot analysis. Most patients ran an aggressive clinical course and five died of the disease. Nonrandom clonal chromosomal abnormalities, including duplication of 1q, rearrangement at 3q and loss of chromosomes Y, 13 or 10, were noted in the six patients from this study and in eight from the literature. The implications of these recurrent cytogenetic aberrations in the development and progression of the disease deserve further studies.     

Recombinant natural killer enhancing factor augments natural killer cytotoxicity

An 18-year-old schizophrenic female was recently treated after overdosing on trihexyphenidyl, thioridazine and an unknown antidepressant. On presentation to a local hospital, she was cyanotic with dilatated pupils and in acute respiratory failure. She was intubated prior to transfer. While in our Emergency Department, she exhibited occasional premature ventricular contractions which later became intermittent torsade de pointes. As this was an anticholinergic overdose we infused sodium bicarbonate in an attempt to increase protein binding, hoping to decrease the concentration of toxic metabolites. We also tried to suppress the dysrhythmia by infusing magnesium. The potassium level was borderline low so a supplemental infusion was initiated. Defibrillation was attempted. To try to shorten the action potential duration by activating the K+ channel, an isuprel infusion was also attempted. All methods failed. The patient fluctuated between an irregular sinus rhythm with prolonged QT interval and pulseless torsade de pointes for almost 24 hours. At all times, she responded appropriately to pain. Finally we attempted blockade of the calcium channel using verapamil with dramatic results. Each single bolus (0.1 mg/kg) successfully converted the patient back to sinus rhythm for some 15-20 minutes before the torsade recurred. After the initiation of a continuous verapamil infusion (0.005 mg/kg/hr), the patient remained in stable sinus rhythm. Verapamil proved highly effective in this patient with an anticholinergic overdose induced dysrhythmia.     

Direct activity of human T lymphocytes and natural killer cells against Cryptococcus neoformans

Lymphocytes constitute a critical component of host defenses against cryptococcosis. Previously, we demonstrated that human lymphocytes cultured with interleukin-2 formed conjugates with, and directly inhibited the growth of, Cryptococcus neoformans. Here, we explore the anticryptococcal activity of freshly isolated, highly purified populations of human peripheral blood lymphocytes. Lymphocytes were incubated with encapsulated C. neoformans for 24 h, after which the lymphocytes were lysed, dilutions and spread plates were made, and CFU were counted. Fungistasis was determined by comparing growth in wells with and without lymphocytes. Nylon wool-nonadherent peripheral blood mononuclear cells (NWNA PBMC) were highly fungistatic, even if either T cells or natural killer (NK) cells were depleted by panning. A mixed population of T cells and NK cells, obtained by rosetting NWNA PBMC with sheep erythrocytes, completely inhibited cryptococcal growth, whereas the nonrosetting cells had little fungistatic activity. CD4+, CD8+, and CD16/56+ lymphocytes, isolated by positive immunoselection, had potent growth-inhibitory activity. In contrast, purified B cells had no activity. Fungistasis was seen even in the absence of opsonins. Antifungal activity was markedly diminished when surface receptors on NWNA PBMC were cleaved by treatment with trypsin or bromelain. Supernatants from stimulated lymphocytes or concentrated lymphocyte sonicates were not active. Lymphocyte-mediated fungistasis was seen with two different strains of C. neoformans. CD4+, CD8+, and CD16/56+ lymphocytes formed conjugates with C. neoformans, as observed under Nomarski differential interference contrast microscopy and videomicroscopy. These data demonstrate that freshly isolated peripheral blood T cells and NK cells have the capacity to bind and directly inhibit the growth of C. neoformans.     

Suppression of natural killer cell activity in mouse spleen lymphocytes by several dopamine receptor antagonists

Glomerular diseases are associated with changes in glomerular membrane permeability properties that alter filtration rate of plasma water and barrier function of the capillary wall. To estimate intrinsic permeability properties that regulate transmembrane transport of water and macromolecules, theoretical analysis of renal clearance of tracer molecules can be used. The development of adequate theoretical models is required to achieve sufficient accuracy to simulate complicated biological processes. Current research in this area is aimed at improving and validating the presently available models in order to characterize the nature of permeability changes associated with pathological conditions. This is a key step in understanding the pathophysiological nature of glomerular diseases and in the development of effective treatments.     

Human natural killer cells

Human natural killer (NK) cells comprise 10 to 15% of peripheral blood lymphocytes, characterized by their morphologic appearance of large granular lymphocytes (LGLs) and phenotype CD3- CD56+ CD16+ or CD16-. Functionally, these cells are defined by their ability to lyse target cells without prior sensitization and without restriction by major histocompatibility (MHC) antigens. These cells play an important role in immune defenses, especially after hematopoietic transplantation. They contribute to the defenses against virus-infected cells, graft rejection, and neoplasias; they also participate in the regulation of hematopoiesis through cytokine production and cell to cell interaction. In this mini-review we attempt to summarize the most relevant findings about these cells in terms of their origin and differentiation, their cell surface characteristics including activation and their cytolytic pathways. We have also provided a brief approach of their potential clinical use. Increased knowledge of NK cell differentiation, ontogeny and regulatory mechanisms may be of use for the planning of immunotherapeutic strategies.     

Antifungal activity of interleukin-2-activated natural killer (NK1.1+) lymphocytes against Candida albicans

Protease inhibitors are currently the most effective antiviral agents against human immunodeficiency virus type 1 (HIV-1). In this study we determined the effect of four HIV-1 protease inhibitors on human T cell leukemia virus type 1 (HTLV-I). Rhesus monkey cells infected with HTLV-I were treated with different concentrations of indinavir, saquinavir, ritonavir, or nelfinavir. The effect of these inhibitors was monitored through their effect on the processing efficiency of the viral Gag protein in cells, the natural substrate for the viral protease. These inhibitors failed to block processing of HTLV-I Gag. To confirm these findings, human cells were cotransfected with plasmids encoding infectious copies of HIV-1 and HTLV-I, and the cells were subsequently treated with these same HIV-1 protease inhibitors. At concentrations between 5 and 50 times the IC50 for inhibition of HIV-1 replication, inhibition of HIV-1 Gag cleavage was apparent. In contrast, no effect on HTLV-I Gag processing was seen. At higher concentrations, HIV-1 Gag processing was essentially completely inhibited whereas HTLV-I Gag cleavage was still unaffected. Thus, these inhibitors are not effective inhibitors of HTLV-I Gag processing. Sequence alignments of the HIV-1 and HTLV-I viral proteases and processing sites suggest that the active site of the HTLV-I protease may have subtle differences in substrate recognition compared with the HIV-1 protease.     

Selective activation of cAMP-dependent protein kinase type I inhibits rat natural killer cell cytotoxicity

The present study examines the expression and involvement of cAMP-dependent protein kinase (PKA) isozymes in cAMP-induced inhibition of natural killer (NK) cell-mediated cytotoxicity. Rat interleukin-2-activated NK cells express the PKA alpha-isoforms RIalpha, RIIalpha, and Calpha and contain both PKA type I and type II. Prostaglandin E2, forskolin, and cAMP analogs all inhibit NK cell lysis of major histocompatibility complex class I mismatched allogeneic lymphocytes as well as of standard tumor target cells. Specific involvement of PKA in the cAMP-induced inhibition of NK cell cytotoxicity is demonstrated by the ability of a cAMP antagonist, (Rp)-8-Br-adenosine 3',5'-cyclic monophosphorothioate, to reverse the inhibitory effect of complementary cAMP agonist (Sp)-8-Br-adenosine 3',5'-cyclic monophosphorothioate. Furthermore, the use of cAMP analog pairs selective for either PKA isozyme (PKA type I or PKA type II), shows a preferential involvement of the PKA type I isozyme, indicating that PKA type I is necessary and sufficient to completely abolish killer activatory signaling leading to NK cell cytotoxicity. Finally, combined treatment with phorbol ester and ionomycin maintains NK cell cytotoxicity and eliminates the cAMP-mediated inhibition, demonstrating that protein kinase C and Ca2+-dependent events stimulate the cytolytic activity of NK cells at a site distal to the site of cAMP/PKA action.     

Immunosuppressive activity of cloned natural killer (NK1.1+) T cells established from murine tumor-infiltrating lymphocytes

To elucidate the role of NK1.1+ T cells in the antitumor immune response, we established cloned NK1.1+ T cell lines from tumor-infiltrating lymphocytes (TIL) of B16 melanoma, and examined their mode of action in generating antitumor effector T cells both in vitro and in vivo. An NK1.1+ T cell clone (TM4.2) was phenotypically CD3+ TCR-alphabeta+ CD4- CD8- NK1.1+, and CD28+. The TM4.2 cells suppressed the in vitro generation of anti-B16 melanoma CTLs, but not the effector function of CTLs. The results using a transwell membrane suggested that their suppressive activity was mediated by both soluble factors and a direct cell to cell interaction. As for the soluble factors, the suppressive activity of the culture supernatant of TM4.2 cells was neutralized by anti-TGF-beta mAb, and the TM4.2 cells actually produced a considerable amount of TGF-beta. On the other hand, the TM4.2 cells showed a high level of cytolytic activity against B cell blasts and CD80-transfected P815, and such cytolytic activity was reduced by the addition of anti-CD80 mAb. In addition, NK1.1+ T cells in the freshly isolated TIL were revealed to express CD28. Furthermore, the TM4.2 cells suppressed the in vitro generation of anti-allo CTLs irrespective of the MHC haplotype. Finally, the TM4.2 cells suppressed the in vivo antitumor immune response. Collectively, these findings demonstrate that NK1.1+ T cells in TIL show immunosuppressive activity in the antitumor immune response through the production of TGF-beta and the preferential cytolysis of B7-expressing cells.     

Control of self-reactive cytotoxic T lymphocytes expressing gamma delta T cell receptors by natural killer inhibitory receptors

The majority of peripheral blood gamma delta T cells in human adults expresses T cell receptors (TCR) with identical V regions (V gamma 9 and V delta 2). These V gamma 9 V delta 2 T cells recognize the major histocompatibility complex (MHC) class I-deficient B cell line Daudi and broadly distributed nonpeptidic antigens present in bacteria and parasites. Here we show that unlike alpha beta or V gamma 9- gamma delta T cells, the majority of V gamma 9V delta 2 T cells harbor natural killer inhibitory receptors (KIR) (mainly CD94/NKG2A heterodimers), which are known to deliver inhibitory signals upon interaction with MHC class I molecules. Within V gamma 9V delta 2 T cells, KIR were mainly expressed by clones exhibiting a strong lytic activity against Daudi cells. In stark contrast, almost all V gamma 9V delta 2 T cell clones devoid of killing activity were KIR-, thus suggesting a coordinate acquisition of KIR and cytotoxic activity within V gamma 9V delta 2 T cells. In functional terms, KIR inhibited lysis of MHC class I-positive tumor B cell lines by V gamma 9V delta 2 cytotoxic T lymphocytes (CTL) and raised their threshold of activation by microbial antigens presented by MHC class I-positive cells. Furthermore, masking KIR or MHC class I molecules revealed a TCR-dependent recognition by V gamma 9V delta 2 CTL of ligands expressed by activated T lymphocytes, including the effector cells themselves. Taken together, these results suggest a general implication of V gamma 9V delta 2 T cells in immune response regulation and a central role of KIR in the control of self-reactive gamma delta CTL.     

Expression of different lipoprotein receptors in natural killer cells and their effect on natural killer proliferative and cytotoxic activity

Natural killer (NK) cells take up chylomicrons (CM), very low density (VLDL), low density (LDL), high density (HDL) and acetyl-modified low density (AcLDL) lipoproteins through different receptors, VLDL being the lipoprotein with the highest uptake and HDL the lowest. The uptake of LDL can be selectively blocked by the anti-LDL receptor, which does not affect the uptake of CM, VLDL, HDL and AcLDL. Although the uptake of lipoproteins assessed by flow cytometry using DiI is not very high, the lipoproteins are able to induce an increase in proliferative responses, VLDL, AcLDL and HDL being the most important ones with 12- and 17-fold increments, respectively. CM, VLDL and LDL at low concentrations increase NK cytotoxic activity, while HDL and AcLDL inhibit, in a dose-dependent fashion, the killing of NK cells against K562. These results suggest the presence of four different receptors that are responsible for the cytotoxic and proliferative responses observed.     

Impaired release of natural killer cytotoxic factor(s) by peripheral blood lymphocytes in patients with chronic LGL-proliferative disease

BACKGROUND: Chronic LGL-proliferative disease (LGL-PD) is a clonal expansion of cells with large granular lymphocyte (LGL) morphology. In most cases, proliferating cells express both suppressor/cytolytic T-cell and natural killer (NK) cell surface markers, but other cell phenotypes may be observed. LGL-PD lymphocytes have been found to lack or show very low natural killer cell activity (NKa). The aim of the present paper is to investigate the underlying mechanisms responsible for impaired NKa in a homogeneous group of five selected LGL-PD patients with a CD3+, CD8+, CD57+ cell phenotype. RESULTS: In all patients, the expanded cell population expressed very low NKa against K562 cell targets, but this increased significantly with recombinant human interleukin-2 (rhIL-2) and phytohemagglutinin (PHA) activation. Recombinant human alpha-interferon (rhIFN-alpha) had no significant effect on NKa. Cells displayed normal tumor cell binding capacity but failed to release sufficient amounts of functionally active natural killer cytotoxic factor(s) (NKCFs) upon interaction with the NK-sensitive K562 cells targets. However, they did release soluble cytolytic molecules against K562 cells upon activation with PHA. CONCLUSIONS: Our findings provide evidence that the defective NKa in LGL-PD patients with the aforementioned phenotype is probably due, at least in part, to the inability of expanded lymphocytes to release NKCFs upon interaction with NK-sensitive cell targets. Since recognition of target cells by patient lymphocytes is not disturbed and the cells are capable of producing NKCFs upon activation with PHA, it is probable that the cause of this abnormality is located at the level of the activation signal provided by the stimulatory target cells. Studies in subcellular level are certainly needed for a more precise determination of the underlying defect.     

Expression of killer cell inhibitory receptors on human uterine natural killer cells

The establishment of the human placenta in early pregnancy is characterized by the presence of large numbers of natural killer (NK) cells within the maternal decidua in close proximity to the fetally-derived invading extravillous trophoblast which expresses at least two HLA class I molecules, HLA-G and HLA-C. These NK cells have an unusual phenotype, CD56(bright) CD16, distinguishing them from adult peripheral blood NK cells. They may control key events in trophoblast migration and therefore placentation. Human NK cells in peripheral blood express receptors for polymorphic HLA class I molecules. This family of receptors, known as killer cell inhibitory receptors (KIR), are expressed on overlapping subsets of NK cells to give an NK cell repertoire which differs between individuals. Using a panel of monoclonal antibodies to several members of the KIR family and analysis by flow cytometry, we have found that KIR are expressed by decidual NK cells. There is variation in both the percentage of cells expressing a particular receptor and the density of receptor expression between decidual NK cells from different individuals. Comparison of NK cells from decidua and peripheral blood of the same individual showed that NK cells from these two different locations express different repertoires of KIR. Receptors are present in individuals who do not possess the relevant class I ligand, raising the possibility that these NK receptors may be involved in recognition of the allogeneic fetus by the mother at the implantation site.     

Semantic memory in Alzheimer's disease and the frontotemporal dementias: A longitudinal study of 236 patients.

Using semantic dementia (SD) as a reference point, the authors assessed semantic memory in four other neurodegenerative disorders: progressive nonfluent aphasia (PNFA), frontal variant frontotemporal dementia (fvFTD), Alzheimer's disease (AD), and posterior cortical atrophy (PCA). Individuals with SD were more impaired than other groups on semantic measures and showed a characteristic pattern across tasks: category fluency (CF) worse than letter fluency (LF), naming worse than comprehension, and visual and verbal comprehension equally affected, suggesting disruption to an amodal semantic system. Individuals with AD demonstrated a similar pattern to a milder degree. Although PNFA, fvFTD, and PCA groups had abnormal scores (relative to controls) on most semantic measures, their differing patterns across measures indicate that the apparent semantic impairment in these conditions is largely secondary to other factors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Defective natural killer cell activity of peripheral blood lymphocytes correlates with the degree of neutropenia in patients with chronic idiopathic neutropenia of adults

Natural killer cell activity (Nka) of peripheral blood mononuclear cells (PBMCs) against K562 cell targets was assessed in 66 patients with chronic idiopathic neutropenia of adults (CINA) using the 16-h 51Cr-release assay. It was found that CINA patients exhibited significantly lower Nkr than normal subjects, which strongly correlated with the degree of neutropenia and the numbers of circulating neutrophils. Patients' NKa was increased by recombinant human interleukin-2 (rhIL-2) or recombinant human interferon-alpha (rhIFN-alpha), but the values obtained did not reach the respective NKa values found in normals. However, percentages of cytokine-induced rises of NKa did not differ statistically between patients and normal subjects. No serum inhibitors of NKa were demonstrated in our patients. CINA patients had low numbers of circulating NK cells as defined by the expression of NK-cell-related surface markers CD16, CD56, and CD57. CD16+ and CD56+, but not CD57+, cells correlated with the values of baseline NKa. The numbers of all these cell subsets correlated with the degree of neutropenia and the numbers of circulating neutrophils. Using CD56+-enriched PBL suspensions, it was shown that patients' NK cells displayed normal tumor cell binding capacity and produced in vitro normal amounts of natural killer cytotoxic factor(s) against K562 cell targets upon activation with rhIFN-alpha. Finally, percentages of perforin-expressing and granzyme B-expressing CD16+ cells did not differ statistically between patients and normal controls. Based on all these observations, we concluded that CINA patients display low NKa probably because they have low numbers of circulating NK cells. No functional abnormalities of NK cells were demonstrated. The cause and the underlying mechanisms leading to NK-cell depletion in these patients remain to be clarified.     

Effect of alpha-tocopherol on the respiratory burst of neutrophils, blast transformation of lymphocytes, and activity of human natural killer cells in blood

The effect of vitamin E on immunological reactions of blood cells was studied. The addition of vitamin E in concentration of 100 microM to neutrophils caused the increase of superoxide production. But this index was decreased when incubation of these cells with A23187 or FMLP was accompanied by alpha-tocopherol in concentration of 100 microM followed by the removal of free ligand or alpha-tocopherol in concentration of 0.5 microM. In the presence of PMA the inhibiting action of alpha-tocopherol was not found (under the 0.5 microM of alpha-tocopherol) or was small (under the concentration of it 100 microM of alpha-tocopherol). The addition of alpha-tocopherol in concentration of 0.5 microM and 50 microM caused the inhibition of blasttransformation of lymphocytes and activity of natural killer cells. This effect was expressed more under the low contents of this vitamin in the incubation medium. The level of blasstransformation of blood in vitamin E-deficient rats was by 20% less than in normal. The exogenous addition of alpha-tocopherol in concentration of 0.5 microM did not affect this value. It was suggested that vitamin E can affect the respiration burst of neutrophils, blasttransformation of lymphocytes and activity of natural killer cells and these actions depend on its concentrations.     

Risk factors of dementia Alzheimer's type

The paper presents the study of risk factors and factors-protectors of the development of dementia of Alzheimer's type (DAT). 40 patients with Alzheimer's disease (AD), 40 patients, with senile DAT and 80 healthy individuals of the same sex, age and education level were examined. The pairs were formed: the patient-normal. The main risk factor in DAT group was family predisposition to dementia. AD risk factors may be the exposure to radioactive materials or chronic psychotraumatic situations during life. Senile DAT risk factors may be traumas of head without lack of consciousness. Acute and frequent psychotraumatic situations as well as some somatic diseases (and related drug therapy) were factors-protectors in the whole DAT group. Groups of patients with AD and senile DAT differed by both risk factors and factors-protectors, confirming DAT heterogeneity. Hypothetic biologic basis of the data obtained is described.     

Effect of eccentric exercise on natural killer cell activity

The effect of eccentric one-legged exercise on natural killer (NK) cell activity was studied in eight healthy males. To distinguish between local and systemic effects, blood samples were collected from veins in the exercising leg and resting arm. However, the results did not significantly differ between the leg and arm. To eliminate diurnal variations, the results were compared with a control group that did not exercise but had blood samples collected at the same time points. In the exercising group, plasma creatine kinase increased progressively during and up to 4 days after exercise. The percentage of CD16+ NK cells increased during exercise, which was paralleled by an increase in the NK cell activity per fixed number of blood mononuclear cells. The NK cell activity on a per NK cell basis did not change. The percentage of CD3+, CD4+, CD8+, CD19+, and CD14+ cells did not change significantly during exercise. The present study thus showed that eccentric exercise with a relatively small muscle mass (1 quadriceps femoris muscle) causes systemic effects on NK cells. It is suggested that the increase in plasma epinephrine during eccentric exercise is responsible for the observed increase in the percentage of CD16+ cells.     

Migratory response of human natural killer cells to lymphotactin

Lymphotactin (Lptn) is a new protein belonging to the C or gamma subfamily of chemokines with only two of the four cysteine residues. Lptn was reported to act specifically on T lymphocytes and not on monocytes and neutrophils. To understand better the spectrum of action of Lptn we have examined its ability to induce natural killer (NK) cell migration. Freshly isolated human NK cells as well as long-term cultured NK cells propagated in interleukin-2 (IL-2)-containing medium migrated in response to Lptn. Optimal activity was observed at concentrations ranging from 50 to 200 ng/ml, and the efficacy was comparable to that of MCP-1, the prototype of C-C chemokines. Migration in response to Lptn was chemotaxis rather than chemokinesis as determined in a checkerboard analysis. Migration of NK cells was comparable to that observed with T lymphocytes from the same donor, under the same experimental conditions. Finally, in contrast to other cytokines (IL-2 and IL-12) which in addition to chemotaxis augment NK cell adhesion to endothelial cells in vitro, Lptn did not affect the adhesiveness of NK cells to vascular endothelium.