Tacrine restores cholinergic nicotinic receptors and glucose metabolism in alzheimer patients as visualized by positron emission tomography

Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [¹⁸F]-fluoro-deoxy-glucose (¹⁸F-FDG) (tracer for glucose metabolism); ¹¹C-butanol (cerebral blood flow) and (S)(−)- and (R)(+)-[N-¹¹C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of ¹¹C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(−)- and (R)(+)¹¹C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(−)¹¹C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.     

Recognition of apoptotic cells by human peripheral blood monocytes does not alter their ability to phagocytize and kill Staphylococcus aureus

INTRODUCTION: During acute inflammation, leukocyte infiltration is mostly neutrophilic, but later monocytes prevail. The majority of inflammatory cells, particularly neutrophilic polymorphonuclear leukocytes (PMNs), become apoptotic at later stages of inflammation and are phagocytosed by neighboring cells, mostly by macrophages. Recently, it has been found that human peripheral blood monocytes also recognize apoptotic cells, which primes them to increased production of interleukin (IL)-10--a cytokine known to reduce phagocytes' ability to engulf and kill pathogens. Based on the above, we studied monocytes' ability to phagocytose and kill Staphylococcus aureus while in contact with apoptotic cells. MATERIALS AND METHODS: Monocytes isolated by elutriation were co-cultured with apoptotic PMNs or Jurkat cells and exposed to viable, human serum-opsonized S. aureus. To induce apoptosis PMNs were cultured overnight while Jurkat cells were UV-treated. Apoptosis, phagocytosis of bacteria and intracellular superoxide production were measured by flow cytometry. Production of reactive oxygen species was also followed by measurement of chemiluminescence. The bactericidal effect was determined by standard colony forming units method. RESULTS: Data presented show that contact of monocytes with apoptotic neutrophils and Jurkat cells had no influence on monocyte phagocytosis of S. aureus, the generation of reactive oxygen species, or the killing of bacteria. CONCLUSION: The data obtained suggest that monocytes attracted to the inflammatory site are not deficient in their ability to cope with pathogens after contact with apoptotic cells despite increased production of IL-10.     

Increase of interleukin 6 and decrease of interleukin 2 production during the ageing process are influenced by the health status

The ageing process is accompanied by the disregulation of interleukin 2 (IL2) and interleukin 6 (IL6) production. In our paper, we asked whether the age between 60 and 70 years is a turning point for the disregulation of both IL2 and IL6 production. Fifty volunteers 60–70 years old, 25 aged 36–59, and 50 of 20–35 years old were enrolled into the study. Their health status was graded according to the criteria of the Senieur Protocol (SP) as ‘healthy' and ‘almost-healthy'. The cytokines level was determined in the sera of the volunteers. Moreover, the spontaneous release of IL6 by peripheral blood mononuclear cells (PBMC) and the activity of the IL6 gene in non-stimulated PBMC were also analysed. Cytokine levels were measured by biological assays, mRNA for IL6 was detected by RT-PCR method. The results showed that the production of IL2 is not disregulated in the ‘healthy' people until the age of 60–70. People not fulfilling all SP criteria are characterised by a lower level of IL2 in the sera. The overproduction of IL6 into the sera and supernatants from non-stimulated PBMC and PBL as well as the activation of IL6 gene start between the ages 36 and 59 and is more pronounced in the ‘almost-healthy'.     

Cell generation within human thymic subsets defined by selective expression of CD45 (T200) isoforms

Although the thymus is the source of all mature peripheral T lymphocytes, the majority of thymocytes die intrathymically. Until recently, there has been no phenotypic marker to allow definition of the generative thymocyte lineage, thereby distinguishing those thymocytes committed to death from those which will evenually give rise to thymic emigrants. We believe that expression of the high-molecular-mass isoforms (p190, p205, and/or p220) of the leukocyte common antigen (CD45) distinguishes the thymic generative lineage from the vast majority of thymocytes expressing the low-molecular-mass isoform (p180) of CD45 and committed to die within the thymus. The thymocytes defined by their lack of CD45 p180, the low-molecular-mass isoform, comprise all thymocytes with clonogenic potential and include all major subsets defined by CD4 and CD8. We have proposed that a CD45 p180⁻ lineage exists in the human thymus and that this lineage results in the production of mature thymocytes and thymic emigrants. The objective of the present study was to determine by DNA analysis whether the degree of cell cycling in subsets of human thymus, defined by selective expression of high-molecular-mass isoforms of CD45, was sufficient to account for the generation of thymic emigrants. Multicolor immunofluorescence analysis of surface markers and 7-amino actinomycin D as well as propidium iodide staing was used to measure the DNA content of thymic subsets. Negative depletion methods were used to isolate and characterize human thymocyte subsets defined by CD45 isoform, CD3, CD4, and CD8, and subsequently to determine the cell cycle status of the isolated subsets by flow-cytometric analysis of cellular DNA content. CD3^−/lo thymocytes had a high number and CD1^−/lo thymocytes a low number of cycling cells, consistent with murine data. CD45 p 180⁻ cells, as well as the CD4⁻8⁻ and CD3⁻4⁻8⁻ subsets which express high molecular-weight CD45 isoforms, exhibited a significant number of cycling cells. Since CD45 p180- thymocytes exhibited a significant number of cycling cells, based on numerical arguments we conclude that this cycling thymocyte fraction is capable of generating the daily requirements of mature thymocytes and thymic emigrants.     

Peanut-induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry

Background

Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%–1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents.

Methods

Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre.

Results

3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004).

Conclusions

The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.

     

What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.     

Vinyl monomer complexes in copolymerization processes. Studies on the complexes of acrylonitrile and methyl methacrylate with lewis acids

Complexes of acrylonitrile and of methyl methacrylate with various Lewis acids, 1 and 2 , were studied by means of IR, NMR, and UV spectroscopy. The influence of the Lewis acid strength on the induction effect and on the delocalization of π-electrons in the complexed monomer molecule was established. As the relative acidity of the complexing agent is increased, the inductive effect of the nitrile or of the carbonyl group in the complex molecule rises, whereby the electron density on the carbon atom in β-position in the vinyl group diminishes. Complexation of the monomer also results in increased delocalization of π-electrons in the molecule. In the complexes with moderately strong Lewis acids like CH₃AlCl₂ and C₂H₅AlCl₂, delocalization of π-electrons seems to reach its maximum. The methyl methacrylate-C₂H₅AlCl₂ complex was found to give a charge-transfer complex with 1,5-cyclooctadiene. On the basis of the present spectroscopic studies and of earlier studies on copolymerization of acryl monomers with butadiene, the delocalization of π-electrons in the complexed monomer molecule is believed to be one of the major factors controlling the rate of copolymerization.     

The results of the interference of nitrates and vitamin E in the metabolism in the connective tissue of rat''s liver

We examined 72 female Wistar rats which were divided into 6 groups. The animals were administered sodium nitrate (V), vitamin E or both compounds at the same time. In order to estimate the interference of nitrates in the presence of vitamin E with the metabolism of rat's liver, we determined the composition and the amount of glycosoaminoglycans (GAGs). It was stated that the total amount of GAGs increased in livers of all rats. Basing on all fractions of the examined GAGs it was determined that the most significant differences between individual groups appeared in the amount of heparane sulphate (HS). The results obtained confirmed the fact of the changes taking place in the picture of liver GAGs in the process of ageing of the examined animals. The results obtained, however, allowed to state the normalising influence of vitamin E on the quantitative composition of GAGs of rats which drank nitrates.     

Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility

BACKGROUND: Male fertility largely depends on the quality of sperm production, which may be affected by environmental and genetic factors. In this study, we explored a possible role of the polymerase gamma (POLG) gene polymorphism, recently reported to be associated with male infertility in some populations. METHODS: The polymorphic CAG repeat (usually 10 codons long) in the POLG gene was studied in 1298 male subjects: 429 patients with infertility/subfertility, and 869 controls (495 men from the general population with unknown fertility and 374 recent fathers). In all subjects, the POLG polymorphism was assessed in relation to their semen quality, and--in the fertile controls--with biological fecundity measured as waiting time-to-pregnancy (TTP) for the couples. In the patients lacking the common POLG allele, the outcome of the assisted reproductive techniques (ART) for the couples was evaluated. RESULTS: The absence of one (10/ not equal to 10) or both common POLG alleles (not equal to 10/not equal to 10) was more frequent among the subfertile patients than among fertile controls (P=0.021 and P=0.04 respectively). The estimated predictive value for infertility in a man homozygous for the POLG polymorphism was 15.5% (95% CI: 4.8-51%). There was a positive association with sperm concentration: 14.3% of the normospermic subfertile patients were homozygous for the absence of the common POLG allele (not equal to 10/not equal to 10), in comparison with 2.3% of unselected controls (P=0.001) and 0.9% of the fertile men (P=0.0001). No association with sperm motility, morphology and TTP was found. Spermatozoa of the three not equal to 10/not equal to 10 patients treated with IVF retained the ability to penetrate the egg, but the fertilization rate was low. Nine homozygous not equal to 10/ not equal to 10 patients were treated with ICSI, resulting in pregnancy in seven couples. CONCLUSIONS: The POLG gene polymorphism should be considered as a possible contributing factor in patients with unexplained subfertility and normal spermiograms. The oocyte penetration ability of sperm may be partially impaired in the not equal to 10/not equal to 10 patients but most of them can be successfully treated with ICSI.     

Type of isoniazid (INH) acetylation determined in tuberculosis patients treated at the Institute of Tuberculosis and Lung Diseases in Warsaw during the years 1990-1997

The researched has dealt with the type of acetylation in 237 TB patients treated with standard course of chemotherapy with a dose of 300 mg of INH in period 1990-1997 in National Research Institute of Tuberculosis and Lung Disease in Warsaw Blood samples were taken before (time 0) and 1, 3, 6 and 24 h after drug administration. Plasma concentrations of isoniazid were determined with biological methods. Two indies of acetylation rate--I3 and C6 have been used to determine an acetylation type. Majority of the treated patients (68.8%) have shown fast type of INH acetylation. After similar dose of isoniazid different profile of absorption and excretion of the drug and significant differences (p < 0.01) in INH concentrations, acetylation rate and bioavailability between 163 fast and 74 slow acetylators have been observed. In plasma of 38.6% fast acetylators drug concentration 3 h after ingestion of a dose did not achieve the concentration of 1 mcg/ml. In plasma of 29.7% slow acetylators, concentrations of INH 6 h after ingestion were higher than 2 mcg/ml.