Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells.

Recent studies have shown inflammatory markers in affected neural tissues of amyotrophic lateral sclerosis (ALS) patients. We examined immunocytochemically spinal cord tissues of six patients with ALS, two with corticospinal tract degeneration secondary to cerebral infarcts and three control subjects without neuropathologic abnormalities. ALS spinal cords had dense macrophage infiltration (one log greater than control spinal cords) involving the white and gray matter, with heaviest infiltration of lateral and ventral columns and, in one patient, prefrontal gyrus and the occipital lobes of the brain. Macrophages in ALS spinal cord showed strong expression of cyclooxygenase-2 (COX-2) (one log greater than control tissues) and inducible nitric oxide synthase. In the gray matter, macrophages surrounded and appeared to phagocytize neurons (NeuN-positive) that appeared to be dying. Vessels showed damage to the tight junction protein ZO-1 in relation to perivascular CD40 receptor-positive macrophages and CD40 ligand-positive T lymphocytes. ALS spinal cords, but not control cords, were sparsely infiltrated with mast cells. In control cases with corticospinal tract degeneration following hemispheric cerebral infarction, macrophage infiltration of the white matter was COX-2-negative and restricted to lateral and anterior corticospinal tracts. Our data suggest that inflammation in ALS spinal cord and cortex is based on innate immune responses by macrophages and mast cells and adaptive immune responses by T cells.     

Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma

Summary The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice — 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) — gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.Abbreviations 5FU 5-fluorouracil - LV leucovorin (folinic acid, 5-formyl-tetrahydrofolate) - FdUMP 5-fluoro 2-deoxyuridine 5monophosphate - TS thymidylate synthase - CH2-THF 5-10 methylenetetrahydrofolate - UR uridine - GDF growth delay factor - TD tumor doubling time - MTD maximum tolerated dose - T/C mean tumor volume of treated mice divided by mean tumor volume of control mice     

Relationship between serum follicle stimulating hormone in the male and standard sperm parameters, and the results of intracytoplasmic sperm injection

Serum follicle stimulating hormone (FSH) is routinely measured when evaluating the infertile male for intracytoplasmic sperm injection (ICSI). However, among the sperm parameters, only its relationship with sperm concentration is well documented. Few investigations concern the relationship between FSH and sperm motility and morphology, and the results of ICSI. A retrospective study of 316 couples who underwent ICSI was carried out to determine the relationships between serum FSH concentrations in the male and (i) standard sperm parameters_(concentration, motility and morphology) and (ii) fertilization, cleavage, pregnancy and implantation rates after ICSI. There was an inverse correlation with sperm concentration and total motility but no relationship was found with progressive motility and sperm morphology. Neither was any relationship found between serum FSH and fertilization, cleavage, pregnancy and implantation rates, and the results of ICSI. These findings suggest the need to review the routine measurement of serum FSH in the infertile male when ICSI is the planned treatment procedure.      

Deep processing activates the medial temporal lobe in young but not in old adults

Age-related impairments in episodic memory have been related to a deficiency in semantic processing, based on the finding that elderly adults typically benefit less than young adults from deep, semantic as opposed to shallow, nonsemantic processing of study items. In the present study, we tested the hypothesis that elderly adults are not able to perform certain cognitive operations under deep processing conditions. We further hypothesised that this inability does not involve regions commonly associated with lexical/semantic retrieval processes, but rather involves a dysfunction of the medial temporal lobe (MTL) memory system. To this end, we used functional MRI on rather extensive groups of young and elderly adults to compare brain activity patterns obtained during a deep (living/nonliving) and a shallow (uppercase/lowercase) classification task. Common activity in relation to semantic classification was observed in regions that have been previously related to semantic retrieval, including mainly left-lateralised activity in the inferior prefrontal, middle temporal, and middle frontal/anterior cingulate gyrus. Although the young adults showed more activity in some of these areas, the finding of mainly overlapping activation patterns during semantic classification supports the idea that lexical/semantic retrieval processes are still intact in elderly adults. This received further support by the finding that both groups showed similar behavioural performances as well on the deep and shallow classification tasks. Importantly, though, the young revealed significantly more activity than the elderly adults in the left anterior hippocampus during deep relative to shallow classification. This finding is in line with the idea that age-related impairments in episodic encoding are, at least partly, due to an under-recruitment of the medial temporal lobe memory system.     

Effects of tibolone on bone quality in ovariectomized monkeys

OBJECTIVE: The purpose of this report is to examine the effects of two doses of tibolone on bone quality (bone biomarkers, bone density, and bone strength) in ovariectomized cynomolgus monkeys fed high-fat diets. DESIGN: Ovariectomized cynomolgus monkeys were randomized into one of five treatment groups: placebo-treated control, tibolone (0.2 mg/kg/day), tibolone (0.05 mg/kg/day), conjugated equine estrogens (Premarin, 0.042 mg/kg/day), and conjugated equine estrogens plus medroxyprogesterone acetate (0.042 and 0.167 mg/kg/day, respectively). Bone quality was assessed by determining bone strength and density in vertebrae and femora collected after 24 months of treatment. RESULTS: Monkeys treated for 24 months with tibolone had increased bone mineral density in the distal femur and improved biomechanical properties in the midshaft femur compared with placebo-treated ovariectomized monkeys, as did monkeys treated with conjugated equine estrogens with or without medroxyprogesterone acetate. No treatment effects were seen in lumbar vertebra bone density or strength. There was no significant difference between tibolone and estrogen on biomechanical properties of the femur. CONCLUSION: These data show that tibolone is comparable to conjugated equine estrogens with or without medroxyprogesterone acetate in decreasing bone turnover and increasing bone strength in ovariectomized monkeys.     

Chloroquine interaction with inflammatory human polymorphonuclear leucocytes

The molecularin vitro association of radiolabelled chloroquine (CQ) with both normal resting and inflammatory polymorphonuclear leucocytes (PMNs) was measured. For this purpose a suitable ligandassocation assay was developed to measure the cell association and the intracellular concentration of CQ. Under the influence of inflammatory stimuli PMNs display altered interaction with CQ. The intracellular concentration of CQ is reduced with 30 to 40% under inflammatory (disease) states when compared with non-inflammatory conditions. The mechanisms of CQ-PMN interaction associated with these altered intracellular concentrations of CQ are considered, with particular attention to the effects of rheumatic disease. Association experiments of CQ with PMNs performed in the presence of different established transport inhibitors showed that both diffusive uptake and carrier-mediated transport are involved in the cell accumulation of CQ in inflammatory PMNs. From these results, emphasis is given to three explanations for the decrease of the intracellular CQ concentration in inflamed PMNs:

1. the expansion of the PMN volume under inflammatory conditions;
2. the cytoplasmic or lysosomal pH changes and activation of the PMN Na⁺/H⁺ antiport by inflammatory stimuli; and
3. the exocytic release of the granules (degranulation).

Our data suggest that all these mechanisms, based on the events involved in inflammatory responses, may be involved in the decrease of the intracellular CQ concentration in inflammatory PMNs.     

Correlation between semen parameters and sperm aneuploidy rates investigated by fluorescence in-situ hybridization in infertile men

Spermatozoa from 32 infertile patients and 13 controls with normal semen parameters were analysed using dual and triple colour fluorescence in-situ hybridization (FISH) techniques, in order to investigate the rates of aneuploidy for chromosomes 13, 18, 21, X and Y. The patients were divided into three groups according to their karyotypes or the karyotypes of their offspring: 15 were infertile men with abnormal semen parameters and normal karyotypes (group 1), 13 were infertile men with abnormal karyotypes and normal or abnormal semen (group 2) and four were infertile men with abnormal semen and normal karyotypes but whose wives conceived a child (or a fetus) with a numerical chromosomal abnormality through an intracytoplasmic sperm injection cycle (group 3). Patients with abnormal semen parameters showed a significantly higher aneuploidy rate for the investigated chromosomes in their spermatozoa compared to controls (P < 0.005). Our data suggest the presence of a correlation between poor semen parameters and an increase in aneuploidy rate of chromosomes 13, 18, 21, X and Y in spermatozoa (r = -0.81071, P < 0.002); therefore the risk of a chromosomal aneuploidy in spermatozoa seems to be inversely correlated to sperm concentration and total progressive motility. Patients with abnormal karyotypes showed a higher incidence of diploidy and chromosomal aneuploidies compared to controls (P < 0.002). This strongly suggests the presence of an interchromosomal effect of the cytogenetic rearrangement. Men who fathered a child with an abnormal karyotype through intracytoplasmic sperm injection did not present a higher aneuploidy rate for the investigated chromosomes in spermatozoa compared to patients with infertility due to a similar male factor but showed higher incidence of chromosomal aneuploidy compared to normal controls.     

Effect of Pyrimidine Nucleosides on Body Temperatures of Man and Rabbit in Relation to Pharmacokinetic Data

The effect of high-dose uridine on body temperatures of rabbits and man has been studied in relation to plasma concentrations of uridine and its catabolite uracil. Uridine induced fever in both rabbits and man. High-dose cytidine had no influence on body temperature in rabbits. Plasma concentrations of uridine were between 1 and 1.5 mM at 30 min after an iv bolus injection of 400 mg uridine/kg in rabbits and reached peak levels of 2 mM after a 1-hr infusion of 12 g uridine/m² in man. The plasma concentration of cytidine in rabbits was about 0.5 mM and that of uridine was 0.30 mM at 30 min after an iv bolus injection of 400 mg cytidine/kg. The mean residence time for uridine in patients and rabbits varied between 80 and 195 min. The area under the plasma concentration–time curve (AUC) for uridine in rabbits was 2.0 mmol · hr/liter, and that for cytidine was 0.6 mmol · hr/liter. A large AUC for uridine indicates a prolonged exposure of tissues to uridine, which might lead to extensive formation of degradation products. The administration of some of these catabolites, dihydrouracil (at 20–40 mg/kg), carbamyl--alanine (at 60 mg/kg), and -alanine (at 300–400 mg/kg), resulted in a significant increase in body temperature. It is concluded that the change in body temperature associated with uridine administration was not due to bacterial pyrogens but that one of the degradation products might be involved in thermoregulation.     

Patients'' complaints and satisfaction 5 years after complete denture treatment

This study is based on an evaluation of patients' opinions of their dentures by means of a questionnaire. The patients had been provided with complete dentures at a university clinic. Of the original sample (n = 139) a test group of 92 patients remained available for the actual study 5 yr after treatment. The replies in the questionnaire were subjected to statistical processing and interpretation. Six clusters could be defined and these were introduced as "scales" representing the patients' score on a specific type of complaint. Apart from the six scales a score was achieved for each patient's overall satisfaction. The correlations between the various scales were calculated with the aid of a computer program. Finally, cross-tabulation was used to see if any significant (inter)correlations could be proved between complaints, satisfaction, and some of the patients' social data. It could be concluded that a correlation exists between complaints of pain and of functional aspects on the one hand and vague complaints on the other hand. There is also a correlation between complaints of looseness of the maxillary denture and complaints about aesthetic factors. Well-fitting and well-functioning dentures, absence of pain, and a socially acceptable appearance contribute much to the patients' satisfaction with dentures. Social variables such as type of insurance (public or private) and marital status influence denture appreciation to a certain extent.