The pharmacological stimulation of NMDA receptors via co-agonist site: an fMRI study in the rat brain

d-Serine has been proposed as an endogenous modulator at the co-agonist glycine-binding site of N-methyl-d-aspartate (NMDA) receptors. There is still some debate as to whether this site is saturated in vivo, but it seems likely that this depends on regional differences in local glycine or d-serine concentrations. In order to identify areas where the co-agonist site was not fully activated in vivo, we studied the effect of intraperitoneal d-serine administration in the rat brain using functional magnetic resonance imaging (fMRI). Using contrast agent injection, the variations in the relative cerebral blood volume (CBVrel) in several regions of interest were evaluated. d-Serine (50 mg/kg) elicited a significant statistical increase in the CBVrel in the hippocampus. This effect was inhibited by the specific full antagonist of the co-agonist glycine site L-701,324 indicating that the hippocampal activation occurred through the binding of the agonist d-serine to the glycine-binding site of NMDA receptors. This result demonstrates that in the hippocampus, the co-agonist sites of NMDA receptors are not endogenously saturated under our experimental conditions, suggesting an important role of d-serine in the modulation of receptor function in the hippocampus.     

Effects of the CDC2 gene on adaptive mutation in the yeast Saccharomyces cerevisiae

We have studied the influence of a temperature-sensitive cdc2-1 mutation in DNA polymerase on the selection-induced mutation occurring at the LYS-2 locus in the yeast Saccharomyces cerevisiae. It was found that in cells plated on synthetic complete medium lacking only lysine, the numbers of Lys⁺ revertant colonies accumulated in a time-dependent manner in the absence of any detectable increase in cell number. When cdc2-1 mutant cells, after selective plating, were incubated at the restrictive temperature of 37°C for 5 h daily for 7 days, the frequency of an adaptive reversion of lys ^- Lys⁺ was significantly higher than the frequency in cells incubated only at the permissive temperature, or in wild-type cells incubated either at 23°C or 37°C. Therefore, when the proof-reading activity of DNA polymerase is impaired under restrictive conditions, the frequency of adaptive mutations is markedly enhanced.     

B-1 cells are pivotal for in vivo inflammatory giant cell formation

The mechanisms that govern giant cell (GC) formation in inflammatory, neoplastic and physiologic conditions are far from being understood. Here, we demonstrate that B-1 cells are essential for foreign-body GC formation in the mouse. GCs were analysed on the surface of glass cover slips implanted into the subcutaneous tissue of the animals. It was demonstrated that GCs are almost absent on cover slips implanted into the subcutaneous tissue of BALB/c or CBA/N X-linked immunodeficient mice. As these animals do not have B-1 cells in the peritoneal cavity, they were reconstituted with B-1 cells obtained from cultures of adherent mouse peritoneal cells. Results showed that in B-1-reconstituted animals, the number of GCs on the implant surface surpassed the values obtained with preparations from wild animals. In animals selectively irradiated (pleural and peritoneal cavities) to deplete these cavities of B-1 cells, GCs were also not formed. Enriched suspensions of B-1 cells grown in culture were labelled with [(3)H]-tymidine and injected into the peritoneal cavity of naive mice before implantation of glass cover slips. After 4 days, about 17% of mononuclear cells had their nuclei labelled, and almost 70% of GCs had one or more of their nuclei labelled when analysed by histoautoradiographic technique. A few GCs expressed an immunoglobulin M when analysed by immunostaining and confocal microscopy. Overall, these data demonstrate that B-1 cells are pivotal in the mechanisms of foreign-body GC formation in the mouse.     

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.     

The yeast VPS genes affect telomere length regulation

Eukaryotic cells invest a large proportion of their genome in maintaining telomere length homeostasis. Among the 173 non-essential yeast genes found to affect telomere length, a large proportion is involved in vacuolar traffic. When mutated, these vacuolar protein-sorting (VPS) genes lead to telomeres shorter than those observed in the wild type. Using genetic analysis, we characterized the pathway by which VPS15, VPS34, VPS22, VPS23 and VPS28 affect the telomeres. Our results indicate that these VPS genes affect telomere length through a single pathway and that this effect requires the activity of telomerase and the Ku heterodimer, but not the activity of Tel1p or Rif2p. We present models to explain the link between vacuolar traffic and telomere length homeostasis.     

P-glycoprotein expression influences the result of 99mTc-MIBI scintigraphy in tertiary hyperparathyroidism

Precise localization of parathyroid glands using 99mTc-labeled hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy could be affected by various biological factors. There is increasing evidence that radiotracer retention could be controlled by members of multidrug resistance (MDR) system, especially P-glycoprotein (P-gp). Since the role of P-gp in tertiary hyperparathyroidism (T-HPTH) scintigraphic studies is poorly recognized, the aim of the study was to compare the correlation between parathyroid P-gp expression and results of their scintigraphy in T-HPTH versus primary hyperparathyroidism (P-HPTH). P-HPTH (n = 19) and T-HPTH (n = 18) patients were subjected to 99mTc-MIBI scintigraphy followed by surgical treatment. The parathyroid glands were assessed in routine hematoxylin-eosin staining and P-gp expression was analyzed using immunohistochemistry. Parathyroids collected during cadaver donor multi-organ harvesting were used as a control. It has been found that P-HPTH-derived parathyroid glands with predominating adenoma morphology expressed less P-gp, as compared to P-gp-rich T-HPTH glands, mainly displaying nodular or diffused hyperplasia phenotype. This finding reversely correlated with results of 99mTc-MIBI scintigraphy. However, we did not observe any difference in P-gp expression nor scintigraphy result between nodular or diffused hyperplasia. Altogether, these data suggest that P-gp overexpression in T-HPTH could be responsible for decreased sensitivity of 99mTc-MIBI scintigraphy in those patients. Therefore, the recently proposed reduced neck exploration or limited parathyroid resection on the basis of scintigraphy could create the risk of persisted/recurrent hyperparathyroidism. However, this problem requires further study.     

Dyadic reciprocal associations between self-efficacy and planning predict sedentary behaviour

Objectives

There are two alternative hypotheses regarding bidirectional associations between self-efficacy and planning in predicting health behaviour change: self-efficacy may establish planning (cultivation hypothesis) or planning may enable the formation of self-efficacy (enabling hypothesis). This study investigates the order in which these two social cognitions are linked in adult–adult dyads in the context of sedentary behaviours (SB).

Design

A longitudinal study with 4 measurement points, spanning 8 months.

Methods

A total of 320 dyads (age: 18–90 years) were enrolled. Dyads included a focus person (who received the recommendation to reduce SB and intended to change their SB), and their partners, who were willing to support the focus persons and intended to reduce their own SB as well. Data were collected at Time 1 (T1), Time 2 (1 week later, T2), Time 3 (T3, 2 months after T1) and Time 4 (T4, 8 months after T1). SB was measured with accelerometers at (T1 and T4). Mediation models with individual and dyadic reciprocal effects were tested with path analyses.

Results

Only one indirect effect was found: A higher level of partners' SB reduction-specific self-efficacy at T2 was related to the focus person's more frequent planning to reduce SB at T3, which, in turn, predicted lower SB time among partners at T4.

Conclusions

The findings provide partial support for the cultivation model (self-efficacy prompting planning) and for dyadic reciprocal associations in the context of SB time reduction among adult dyads.     

Primary and acquired drug resistance of tuberculosis bacilli in Poland

Information about resistant pattern of Mycobacterium tuberculosis isolates against antituberculon drugs is a very important part of tuberculosis control and indicates the directions of TB policy in each country. Poland joined WHO/IUATLD global project on drug resistance surveillance, and carried out the first prospective survey, simultaneously on primary and acquired drug resistance of tuberculosis patients according WHO/IUATLD recommendations. The programme covered the whole country, basing on cooperation between the National Reference Laboratory (NRL) with regional TB laboratories. Questionnaires and cultures were obtained from patients who excreted TB bacilli during the period from 1 November 1996 to 1 November 1997 (12 months). Drug susceptibility testing to INH, SM, EMB and RMP were performed on Lowenstein-Jensen medium according to the proportion method or/and radiometric Bactec 460 TB system. 3970 TB patients bacteriologically confirmed by culture were included in a one-year study. The male to female ratio was 2.6:1. Patients were at the age of 6 to 83 years. Majority of patients (86% males and 77% of females) was older than 35 years. Primary resistance to any drug was found in 3.6% of new cases and 2.4% of those patients who excreted monoresistant strains. No monoresistance to EMB was found. 18 patients (0.6%) were infected by MDR strains. Total resistance in new cases was for INH--2.6%, for SM--1.8%, for RMP--0.7% and for EMB--0.1%. Acquired resistance to any drug was found in 17.0% of treated. Majority of patients--7.7% excreted monoresistant strains. 7.0% were infected by MDR strains. Total resistance to INH was 14.8%, to SM--9.2%, to RMP--7.8%, and to EBM--2.5%. No correlation was found between sex and primary resistance rates. Among new cases, 3.7% of males and 3.3% of females were infected with resistant strains. However, among treated patients, males (20%) excreted resistant strains twice as much as females (9.1%). Mean age of women and men infected with primary and acquired resistant strains was similar.