Biomedical subjects

J Andersson

Publications and source records attributed to J Andersson.

At least 109 records · Page 6Linked to original sources

PubMed1999

Effects of repeated apneas on apneic time and diving response in non-divers.

Human breath-hold divers usually perform a series of dives with short intervals. Repeated apneas prolong apneic time, and an accentuated diving response has been suggested to be the cause. The aim of this study was to investigate the effect of repeated apneas on apneic time and diving response in humans. Forty-one subjects performed a series of five apneas with face immersion in water of 10 degrees C, separated by 2-min intervals. Apneas were performed at rest and to individual maximal duration. Heart rate, mean arterial pressure, skin capillary blood flow, and respiratory movements were recorded. Thirty-eight of the subjects were used for analysis of cardiovascular parameters, and in 23 subjects the physiologic breaking point could be detected by the involuntary breathing movements. Heart rate reduction and blood pressure increase were most prominent during the first apneic face immersion, whereas skin capillary blood flow reduction was most intense in the second apneic face immersion. Blood pressure and skin capillary blood flow during recovery from apneic episodes also changed throughout the series. Repetition increased apneic time by 55% and postponed the occurrence of involuntary breathing movements by 27% in subjects passing the physiologic breaking point. We conclude that both physiologic factors, associated with the accumulation of CO2, and psychologic factors, related to the capacity to withstand the respiratory drive, contribute to the prolongation of apneic time whereas an increased diving response does not contribute.

Adult↗

PubMed1998

Localization and characterization of two nucleotide-binding sites on the anaerobic ribonucleotide reductase from bacteriophage T4.

We have used 8-azidoadenosine 5'-triphosphate (8-N3ATP) to investigate the nucleotide-binding sites on the NrdD subunit of the anaerobic ribonucleotide reductase from T4 phage. Saturation studies revealed two saturable sites for this photoaffinity analog of ATP. One site exhibited half-maximal saturation at approximately 5 microM [gamma-32P]8-N3ATP, whereas the other site required 45 microM. To localize the sites of photoinsertion, photolabeled peptides from tryptic and chymotryptic digests were isolated by immobilized Al3+ affinity chromatography and high performance liquid chromatography and subjected to amino acid sequence and mass spectrometric analyses. The molecular masses of the photolabeled products of cyanogen bromide cleavage were estimated using tricine-SDS-polyacrylamide gel electrophoresis. Overlapping sequence analysis localized the higher affinity site to the region corresponding to residues 289-291 and the other site to the region corresponding to residues 147-160. Site-directed mutagenesis of Cys290, a residue conserved in all known class III reductases, resulted in a protein that exhibited less than 10% of wild type enzymatic activity. These observations indicate that Cys290 may reside in or near the active site. High performance liquid chromatography analysis revealed that photoinsertion of [gamma-32P]8-N3ATP into the site corresponding to residues 147-160 was almost completely abolished when 100 microM dATP, dGTP, or dTTP was included in the photolabeling reaction mixture, whereas 100 microM ATP, GTP, CTP, or dCTP had virtually no effect. Based on these nucleotide binding properties, we conclude that this site is an allosteric site analogous to the one that has been shown to regulate substrate specificity of other ribonucleotide reductases. There was no evidence for a second allosteric nucleotide-binding site as observed in the anaerobic ribonucleotide reductase from Escherichia coli.

Adenosine Triphosphate↗

PubMed1998

Erratum to "Immunocytochemical detection of cytokines and chemokines in Langerhans cells and in vitro derived dendritic cells".

We have developed a direct immunocytochemical technique to identify cytokine and chemokine production in epidermal Langerhans cells (LC) and in vitro derived CD14-, CD1a+, CD83+, CD40+ dendritic cells (DC) at the single cell level. Formaldehyde fixation combined with saponin permeabilization preserved cellular morphology and generated a characteristic juxtanuclear staining signal due to the accumulation of cytokine to the Golgi organelle. This approach was used for the assessment of TNF-alpha, IL-6, IL-8, IL-10, IL-12, GM-CSF, MIP-1alpha, MIP-1beta and RANTES producing cells. In contrast, a diffuse cytoplasmic staining was evident for IL-1ra, IL-1alpha and IL-1beta production. IL-1ra and IL-1alpha were expressed in 10-25% of unstimulated cultured cells, while all the other cytokines were undetectable. IL-1ra, IL-1alpha and IL-1beta were also the dominating cytokines, expressed in up to 85% of the DC, after 3 h of LPS stimulation. A significantly lower number of cells (0-5%) synthesized TNF-alpha, IL-6, IL-10, IL-12 and GM-CSF. The incidence of chemokine producing cells (IL-8, RANTES, MIP-1alpha, MIP-1beta) peaked 10 h after LPS stimulation in up to 60% of the DC. Both immature CD83- and mature CD83+ DC as well as LC had a similar cytokine production pattern. Thus, in comparison to monocytes, LPS stimulation of DC generated a lower incidence of TNF-alpha, IL-6, IL-10 and IL-12 producing cells while IL-1 was expressed in a comparable number of cells.

Antigens, CD↗

PubMed1998

Activated murine B lymphocytes and dendritic cells produce a novel CC chemokine which acts selectively on activated T cells.

Genes were isolated using the suppression subtractive hybridization method by stimulation of pro/pre B cells with anti-CD40 and interleukin (IL)-4 to mature S mu-Sepsilon-switched cells. One of the strongly upregulated genes encodes a novel murine CC chemokine we have named ABCD-1. The ABCD-1 gene has three exons separated by 1. 2- and 2.7-kb introns. It gives rise to a 2.2-kb transcript containing an open reading frame of 276 nucleotides. Two polyadenylation sites are used, giving rise to cDNAs with either 1550 or 1850 bp of 3' untranslated regions. The open reading frame encodes a 24 amino acid-long leader peptide and a 68 amino acid-long mature protein with a predicted molecular mass of 7.8 kD. ABCD-1 mRNA is found in highest quantities in activated splenic B lymphocytes and dendritic cells. Little chemokine mRNA is present in lung, in unstimulated splenic cells, in thymocytes, and in lymph node cells. No ABCD-1 mRNA is detected in bone marrow, liver, kidney, or brain, in peritoneal exudate cells as well as in the majority of all unstimulated B lineage cells tested. It is also undetectable in Concanavalin A-activated/IL-2-restimulated splenic T cells, and in bone marrow-derived IL-2-induced natural killer cells and IL-3-activated macrophages. Recombinant ABCD-1 revealed a concentration-dependent and specific migration of activated splenic T lymphoblasts in chemotaxis assays. FACS(R) analyses of migrated cells showed no preferential difference in migration of CD4(+) versus CD8(+) T cell blasts. Murine as well as human T cells responded to ABCD-1. Freshly isolated cells from bone marrow, thymus, spleen, and lymph node, IL-2-activated NK cells, and LPS-stimulated splenic cells, all did not show any chemotactic response. Thus, ABCD-1 is the first chemokine produced in large amounts by activated B cells and acting selectively on activated T lymphocytes. Therefore, ABCD-1 is expected to play an important role in the collaboration of dendritic cells and B lymphocytes with T cells in immune responses.

Amino Acid Sequence↗

PubMed1998

Early reduction of immune activation in lymphoid tissue following highly active HIV therapy.

OBJECTIVE: To evaluate immune reconstitution within HIV-infected lymphoid tissue during highly active antiretroviral therapy (HAART). DESIGN AND METHODS: In situ cellular responses were studied in sequential tonsillar biopsies in three asymptomatic HIV-infected (CD4 cells greater than 400 x 10(6)/l) antiretroviral treatment-naive volunteers enrolled in a clinical trial to determine the early effect of HAART. Computerized image analysis was used to study immunohistochemically stained sequential tonsil sections for the patterns of local cytokine production, chemokine receptor expression and cellular distribution. Replicate quantitative assessments of samples before and after 4 weeks of therapy were used for the evaluation of drug effects and compared with four uninfected controls. Tonsillar HIV proviral-DNA was determined by fluorescent in situ 5'-nuclease assay. RESULTS: HIV-infected tonsil tissue was characterized by extensive pro-inflammatory and type 1 cytokine expression. A five- to 15-fold elevation of interleukin (IL)-1 alpha, IL-12, IL-2 and interferon (IFN)-gamma protein expression was found compared with controls, and each encompassed a mean of at least 4.5% of the tissue compartment. This was reduced by 20-90% in all individuals after 4 weeks of HAART. In contrast, type 2 cytokine expression (IL-4, IL-10), plus tumour necrosis factor (TNF)-alpha, remained low throughout the study. HAART reduced, by 40%, the expression of HIV co-receptors, CCR5 and CXCR4, which initially were elevated four to six times over the control values. In addition, the myelomonocytic inflammatory proteins, CD68 and calprotectin, diminished by 26-83% after therapy. The HIV RNA was reduced to undetectable levels in plasma by HAART. However, a large pool of tonsil cells (2-7%), remained HIV DNA positive after 4 weeks of therapy. CONCLUSIONS: Although immune activation may be the direct consequence of HIV replication, HAART-associated reconstitution begins with a reduction in inflammatory cytokine production which precedes the elimination of local proviral reservoirs.

Anti-HIV Agents↗

PubMed1998

Immunocytochemical detection of cytokines and chemokines in Langerhans cells and in vitro derived dendritic cells.

Chemokines↗

PubMed1998

Expression level of a transgenic lambda2 chain results in isotype exclusion and commitment to B1 cells.

Two new lambda2 chain-transgenic mouse lines were established, both of which showed stable transgene expression during aging of the mice. The line L23, which expressed the transgene at low levels, exhibited normal B cell development, antibody responses and serum Ig levels. Most of the B cells in this mouse line co-expressed the transgenic lambda2 chain together with an endogenous kappa chain, thus showing poor allelic exclusion of endogenous L chains. On the other hand, high expression of the transgenic lambda2 chain in the other mouse line, L2, resulted in nearly complete exclusion of endogenous L chain isotypes. In this line, the lambda2 transgene was already detectable in the cytoplasm of all preB-II cells and some pro/preB-I cells. Its expression during these early phases obviously inhibited development of conventional B2 cells, since the B cells in the periphery of these mice were almost exclusively of the B1 type. This finding was confirmed by adoptive transfer of transgenic bone marrow into lethally irradiated recipients. Very few B cells were present in the spleen of such recipients. The serum IgM levels of L2 mice were close to normal and the majority of these IgM were associated with the transgenic lambda2 chain. Antibody responses to thymus-dependent antigens in such mice were almost exclusively found to be of IgM class. Together, these findings indicate a developmental bias leading to a predominance of B1 cells in the L2 line.

Adoptive Transfer↗

PubMed1998

Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity.

The transit of immature to mature sIgM+ B cells, the life span, maturation kinetics and response to polyclonal activators have been analyzed with the help of a new mAb (493), that distinguishes immature, 493+ from mature, 493 B cells in a variety of mouse strains tested. Analysis of the turnover of immature 493+ B cells by bromodeoxyuridine (BrdU) labeling kinetics indicate that only 10-20 % of the cells reach the spleen as immature 493+ cells. The life span of 493+ B cells in bone marrow and spleen is around 4 days. BrdU chase experiments show that most of the immature cells in spleen enter the pool of mature, 493+ B cells where they gain a longer life span of 15-20 weeks. Immature and mature B cells respond equally well to LPS stimulation; anti-CD40, however, stimulates mature B cells better than immature B cells. IgM cross-linking of mature B cells results in proliferation, while it induces apoptosis in immature B cells. This apoptosis of immature cells can be inhibited by costimulation with anti-CD40 or by overexpression of bcl-2. We speculate that Ig receptor ligand-mediated apoptosis (negative selection) plays a major role in the transit of immature B cells from bone marrow to spleen, but only a minor role in the transit from immature B cells to mature B cells in the spleen.

Animals↗

PubMed1998

Effects of lung volume and involuntary breathing movements on the human diving response.

The effects of lung volume and involuntary breathing movements on the human diving response were studied in 17 breath-hold divers. Each subject performed maximal effort apnoeas and simulated dives by apnoea and cold water face immersion, at lung volumes of 60%, 85%, and 100% of prone vital capacity (VC). Time of apnoea, blood pressure, heart rate, skin capillary blood flow, and fractions of end-expiratory CO2 and O2 were measured. The length of the simulated dives was the shortest at 60% of VC, probably because at this level the build up of alveolar CO2 was fastest. Apnoeas with face immersion at 100% of VC gave a marked drop in arterial pressure during the initial 20 s, probably due to high intrathoracic pressure mechanically reducing venous return. The diving response was most pronounced at 60% of VC. We concluded that at the two larger lung volumes both mechanical factors and input from pulmonary stretch receptors influenced the bradycardia and vasoconstriction, resulting in a nonlinear relationship between the breath-hold lung volume and magnitude of the diving response in the near-VC range. Furthermore, the involuntary breathing movements that appeared during the struggle phase of the apnoeas were too small to affect the diving response.

Adult↗

PubMed1998

Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission.

Sexually transmitted diseases, genital ulcer disease, and progesterone therapy increase susceptibility to lentivirus transmission. Infection of cells by human immunodeficiency virus (HIV) is dependent on expression of specific chemokine receptors known to function as HIV co-receptors. Quantitative kinetic reverse transcription-polymerase chain reaction was developed to determine the in vivo expression levels of CCR5, CXCR4, CCR3, CCR2b, and the cytomegalovirus-encoded US28 in peripheral blood mononuclear cells and cervical biopsies from 12 women with and without sexually transmitted diseases, genital ulcer disease, and progesterone-predominant conditions. Our data indicate that CCR5 is the major HIV co-receptor expressed in the female genital tract, and CXCR4 is the predominantly expressed HIV co-receptor in peripheral blood. CCR5 mRNA expression in the ectocervix was 10-fold greater than CXCR4, 20-fold greater than CCR2b, and 100-fold greater than CCR3. In peripheral blood, CXCR4 expression was 1.5-fold greater than CCR5, 10-fold greater than CCR2b, and 15-fold greater than CCR3. US28 was not expressed in cervical tissue despite expression in peripheral blood mononuclear cells from five individuals. CCR5 was significantly increased (p < 0.02) in biopsies from women with sexually transmitted diseases and others who were progesterone predominant. In vitro studies demonstrate that progesterone increases CCR5, CXCR4, and CCR3 expression and decreases CCR2b expression in lymphocytes and monocytes/macrophages. Characterization of chemokine receptors at the tissue level provides important information in identifying host determinants of HIV-1 transmission.

Adult↗

PubMed1998

Bacteraemia during the aplastic phase after allogeneic bone marrow transplantation is associated with early death from invasive fungal infection.

Episodes of bacteraemia during the aplastic phase were studied in 500 allogeneic bone marrow (BMT) recipients, regarding incidence, microbial aetiology, risk factors, mortality and causes of death. One hundred and sixty-four patients (33%) had at least one positive blood culture. Gram-positive cocci (alpha-streptococci and coagulase-negative staphylococci) were found in 146/164 cases (89%). Gram-negative bacteria were present in only seven cases. Receiving marrow from an unrelated donor was the only significant risk factor for bacteraemia in univariate regression analysis. Within 60 days after BMT, 69/500 patients died. The mortality rate was significantly higher among those with positive blood cultures during the aplastic phase, 44/164 (27%) than in those without bacteraemia, 25/336 (7%). Death directly caused by sepsis was unusual in patients with alpha-streptococci or CNS-bacteraemia (8/146, 5%). In contrast, three of seven patients with gram-negative bacteraemia died of the infection. However, in patients with bacteraemia, 21 of 44 deaths were attributable to invasive fungal infections (18 candida, three aspergillus; autopsy findings). Among patients with negative blood cultures during the aplastic phase, 6/25 died of invasive fungal infection (three candida, one saccharomyces and two aspergillus). This indicates that early bacteraemia is associated with death from invasive fungal infection. Therefore, efforts to shorten the neutropenic period after BMT, prevention, early detection of invasive fungal infections and adjustments of immunosuppressive regimens when marrow from an unrelated donor is used, may improve the outcome after BMT.

Adolescent↗

PubMed1998

Down-regulation of lymphokine synthesis by intravenous gammaglobulin is dependent upon accessory cells.

We have investigated one mechanism by which pooled human IgG preparations for intravenous use (i.v.Ig) selectively down-regulates lymphokine synthesis. Effects of i.v.Ig on cytokine production were quantified at a cellular level by using an immunocytochemical staining technique. Pure T-lymphocyte preparations (from the peripheral blood of healthy adults) were separated by the use of magnetic beads and were then used in parallel experiments with unfractionated mononuclear cells (MNC). Cell activation was induced either by a combination of the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), and the calcium ionophore, ionomycin, or by direct ligation of the T-cell receptor, using immobilized anti-CD3 monoclonal antibody (MoAb). Cells were cultured in the presence or absence of i.v.Ig and subsequently harvested and stained for the following cytokines: interleukin-2 (IL-2), interferon-gamma (IFN-gamma), tumour necrosis factor-beta (TNF-beta) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Assessment of the frequencies of positively stained cells was performed by manual microscopy and by computerized image analysis. Activation by PMA/ionomycin or by immobilized anti-CD3 MoAb induced substantial lymphokine production in both MNC and in purified T cells. Addition of i.v.Ig led to a diminished synthesis of all of the T-cell products studied in unfractionated MNC preparations, whereas production was maintained or occasionally increased in the purified T-cell preparations. These findings indicate that the immunomodulatory effect by i.v.Ig on T-cell activation and lymphokine production was dependent on accessory cells.

Adult↗

PubMed1998

Lack of T-lymphocytosis and poor interferon gamma production in BAL fluid from HIV-negative immunocompetent patients with pulmonary non-tuberculous mycobacteriosis.

Very little is known about the pathogenesis of pulmonary non-tuberculous mycobacteriosis in immunocompetent individuals. Local inflammatory response was assessed by examining bronchoalveolar lavage fluid from 13 HIV-negative patients (12 F) without known cell-mediated immunosuppression, aged 48-72 y (median age 60 y), with non-tuberculous lung mycobacteriosis. Macrophages, lymphocytes, polymorphonuclear neutrophils and eosinophils in bronchoalveolar lavage fluid were analysed morphologically, and the subsets of T-lymphocytes (CD3+, CD4+, CD8+), HLA-DR+, B-lymphocytes (CD19+) and CD16+/CD56+ cells (natural killer, NK cells) were analysed by flow cytometry. Interleukin-1 beta (IL-1beta), IL-2, IL-4, IL-6, IL-8, IL-10 and interferon-gamma (IFN-gamma) levels were assessed by ELISA. The total number of cells/ml was significantly higher in BAL fluid from the patients (median value=880 x 10(3)/ml) compared to six healthy controls (200 x 10(3)/ml). The polymorphonuclear neutrophil population was significantly increased in the patients both proportionally and in the count/ml. The proportion of macrophages was significantly reduced in the patients but not the count/ml. The count of lymphocytes/ml was significantly higher in the patients but the proportion of lymphocytes was unchanged. No significant difference was seen in the relative proportion of NK cells, B- or T-lymphocytes and HLA-DR+ compared to the healthy controls. The IL-1beta and IL-8 levels were significantly increased in the patients. No differences were seen between the patients and controls in the leukocyte or lymphocyte subsets in peripheral blood. The local inflammatory response in BAL fluid from the studied patients was characterized by granulocytosis, and increase in the IL-1beta and IL-8 levels. There was no specific T-cell response.

Aged↗

PubMed1998

Cognition as a bridge between signal and dialogue: communication in the hearing impaired and deaf.

This paper is an overview of the research we have carried out at Linköping University on cognitive aspects of visual language processing and related communicative forms. In the first section, a cognitive individual difference perspective on speechreading is introduced. In the second, compensatory perceptual mechanisms are discussed on the basis of behavioral and neurophysiological data. The third section addresses further the issue of perceptual versus cognitive compensation, and the fourth and fifth sections apply a set of cognitive tests based on the concept of working memory for poorly specified language input to data on the successes and failures with cochlear implants, tactile aids and hearing aids.

Cognition↗

PubMed1998

Varying titers of neutralizing antibodies to streptococcal superantigens in different preparations of normal polyspecific immunoglobulin G: implications for therapeutic efficacy.

Inasmuch as normal intravenous polyspecific immunoglobulin G (IVIG) neutralizes the activity of a wide spectrum of superantigens, it may be an efficient adjunctive therapy for diseases associated with superantigen-producing organisms, including severe group A streptococcal diseases. The neutralizing activity against purified superantigens, streptococcal pyrogenic exotoxins (Spe), and a mixture of superantigens present in culture supernatant of clinical group A streptococcal isolates was determined for five IVIG preparations. A significant variation among different IVIG preparations (P < .05) and different lots of the same IVIG brand (P < .044) was found. Neutralization of SpeA activity was significantly lower than that of other streptococcal superantigens (P < .05); however, there was no correlation between SpeA binding and SpeA neutralizing activity in different IVIGs. Plasma samples obtained from patients after IVIG infusion varied in their titers of neutralizing antibodies to culture supernatants prepared from their respective isolates, and this variation paralleled differences in the neutralizing titer of the IVIG lot administered to each patient studied. The study suggests that complete neutralizing activity may be achieved by optimizing the type and/or dose of IVIG used in treatment.

Antibodies, Bacterial↗

PubMed1998

Epidemiological and clinical aspects of invasive group A streptococcal infections and the streptococcal toxic shock syndrome.

In a retrospective study of invasive infections due to group A Streptococcus (GAS) in Stockholm during 1987 to 1995, the average incidence per 100,000 residents per year was 2.3, varying between 3.7 per 100,000 (in 1988) and 1.3 per 100,000 (in 1993). Incidence was 1.8 in the age group of 0-4 years but otherwise increased by age, from 0.48 in the age group of 5-14 years to 6.1 among those over 65 years of age. A review of 151 invasive episodes occurring in 1983-1995 showed cyclic increases of infections due to T1M1-serotype strains during 1986-1990 and 1993-1995. The T1M1 serotype accounted for 27 (20%) of 135 available GAS strains. Streptococcal toxic shock syndrome (STSS) developed in 19 (13%) of the 151 episodes. The case fatality rate was 11% overall but 47% among patients with STSS. In a multivariate logistic regression model, STSS was associated with a history of alcohol abuse (odds ratio [OR], 6.3; P = .004) and infection with a T1M1 strain (OR, 6.7; P = .007). Case fatality was associated with age (OR, 14.5; P = .08), immunosuppression (OR, 4.7; P = .02), and STSS (OR, 21.5; P < .0001) but not with T1M1 infection. Hypotension was significantly associated with a fatal outcome, regardless of whether STSS developed (P < .0001).

Adolescent↗

PubMed1998

Fetal liver organ cultures allow the proliferative expansion of pre-B receptor-expressing pre-B-II cells and the differentiation of immature and mature B cells in vitro.

We describe the phenotypic and functional properties of B lineage cells developing in fetal liver organ cultures (FLOC) of mouse embryos at day 14 or 15 of gestation which contain pro/pre-B-I cells. FLOC B cell development proceeds to mature IgM+, IgD+ and CD23+ lipopolysaccharide-reactive B cells within a culture period of 5-6 days. The phenotypes and relative proportions of pro/pre-B-I, pre-B-II, immature and mature B cells from FLOC were similar to that seen in livers freshly isolated from age-matched, i.e. newborn, mice. More importantly, the numbers of cells recovered in the different B lineage subpopulations from FLOC were close to those developed in vivo. Hence, in contrast to single-cell suspension cultures of fetal liver, FLOC allow the proliferative expansion of pre-B cell receptor-expressing pre-B-II cells. FLOC from embryos of mice with targeted mutations in the RAG-2 and lambda5 genes, which cannot expand by proliferative expansion of their pre-B-II compartment in vivo because they cannot express a pre-B cell receptor on their surface, show this same defect in vitro. FLOC are accessible to the action of mAb and cytokines. Thus, addition of anti-IL-7 receptor mAb to FLOC of normal mice inhibits B cell development at the transition of pro/pre-B-I to pre-B-II cells. This inhibition is reversed by addition of excess rIL-7. Addition of IL-7 alone stimulates the proliferation of pro/pre-B-I cells and inhibits their differentiation to pre-B-II and immature B cells, as it does in single-cell suspension cultures. FLOC should be useful to study the effects of other mAb, cytokines, ligands and other molecules on early B cell development.

Animals↗

PubMed1998

Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities.

The effect of long-term treatment with tacrine (tetrahydroaminoacridine) was studied in three Alzheimer patients (aged 57, 64, and 68 years) with mild dementia. All three patients had a Mini-Mental State Examination score of 24/30 and carried at least one apolipoprotein E (ApoE) epsilon4 allele. Tacrine was given in doses between 80 and to 160 mg daily for 13-31 months. A lower tacrine concentration was observed generally in cerebrospinal fluid (CSF) compared with plasma. The acetylcholinesterase activity in CSF tended to be increased following longer periods of tacrine treatment, whereas the butyrylcholinesterase activity was decreased. The three patients repeatedly underwent positron emission tomography investigation of cerebral blood flow, nicotinic receptors, cerebral glucose metabolism, and electroencephalogram (EEG) and cognitive tests. Positive influences on these parameters were observed following both short-term and long-term treatment with tacrine. Improvement of nicotinic receptors (measured as 11C-nicotine binding), cerebral blood flow, EEG, and some cognitive tests (trail making test, block design test) occurred earlier after initiation of tacrine treatment compared with the glucose metabolism, which was increased after several months of tacrine treatment. An improvement in attention (trail making test) was observed following tacrine as sign for frontal lobe activation (EEG). The functional effects of tacrine in Alzheimer patients appeared to be related to both dose and length of cholinesterase inhibitor treatment.

Aged↗