Time course of proliferation and elimination of microglia/macrophages in different neurodegenerative conditions

Ablation of the hindlimb area of the sensorimotor cortex produces degeneration in the cortex (invasive traumatic injury) and leads to retrograde and/or anterograde degeneration in the thalamus (non-invasive injury, distal reaction). This provides an useful model to study the proliferation and elimination of microglia/macrophages in different neurodegenerative conditions. Changes in the morphology, distribution and numbers of microglia in the affected cortex and thalamus were analyzed at various time points (12 h to 30 days) after injury. In parallel, proliferation was determined by immunocytochemistry for the proliferating cell nuclear antigen and cell death by the TUNEL method. Proliferation was an early event in the microglia/macrophage response (from 12 h in the cortex and from 2 days post-lesion in the thalamus) and persisted up to 30 days. The different microglia/macrophage phenotypes proliferated in a specific temporospatial pattern. In the lesioned cortex, early activation and proliferation of intrinsic microglia was accompanied, from the second post-lesion day, by monocyte entrance and proliferation of monocyte-derived cells. In contrast, accumulation of cells in the thalamus resulted from proliferation of intrinsic microglia, without apparent/significant monocytic recruitment. During the subsequent microglia/macrophages removal the majority of the cells in the cortex transformed into ameboid cells devoid of cell processes that progressively accumulated as fully-developed macrophages tissue within the lesion (3-14 days) ultimately migrating out to the meningeal connective tissue (14-30 days). Only some process-bearing cells, remaining in the cortical tissue bordering the lesion, underwent degeneration by 14-21 days post-lesion. In contrast, in the distal affected thalamic nuclei, microglial cell death occurred by 14-30 days post-lesion. Altogether, this study shows that both the origin and fate of microglia/macrophages depend on the nature of the lesion.     

Validity of bone mineral density measurements in distal sites as an indicator of total bone mineral density in a group of pre-adolescent and adolescent women

BACKGROUND: The study of bone mineral density (BMD) has received attention due to the importance of osteoporosis as a public health problem in Mexico. The objective of this study was to assess the validity of BMD measures in distal forearm and calcaneus with portable densitometers as indicators of BMD on other anatomic sites. METHODS: We conducted a cross-sectional study with 219 women from 9 to 22 years of age in Cuernavaca, Morelos, Mexico. We measured BMD in central sites (the entire skeleton, excluding head, proximal femur, and lumbar spine) using dual X-ray absorptiometry (DXA) and in peripheral sites (distal forearm and calcaneus) using a portable densitometer with DXA technology. Measurements of height, weight, body composition, physical activity, and demographic characteristics were collected. Agreement of measurements of BMD was assessed using correlation and regression analysis, and the method proposed by Bland and Altman. RESULTS: Higher levels of BMD were found in total skeleton (0.88 g/cm(2)) than in calcaneus (0.48 g/cm(2)) and distal forearm (0.38 g/cm(2)) (p <0.05). Moderate-to-high positive correlation coefficients (all significant) (p <0.05) were found between BMD in distal forearm and calcaneus vs. central anatomic sites, ranging from r = 0.49 to r = 0.78. BMD was higher in central sites compared with distal forearm and calcaneus. CONCLUSIONS: Measurement of BMD in distal forearm and calcaneus with portable densitometers provided valid indicators of BMD in central anatomic sites among pre-adolescent and adolescent women in Mexico.     

Soluble interleukin 2 receptor (sIL2R) in monitoring advanced lung cancer during chemotherapy

STUDY OBJECTIVES: To evaluate the usefulness of measuring sIL2R for diagnostic and prognostic purposes and for monitoring disease during a 6-month period of chemotherapy, and to investigate the clinical significance of sIL2R serum concentrations. METHODS: The serum concentration of sIL2R, TPA and lymphocyte subsets CD4, CD8, CD25, CD16 were measured at diagnosis and then 1 and 6 months after the start of chemotherapy. PATIENTS: There were 39 patients (three females, 36 males; mean age 61.6 years) with lung cancer (LC), treated with chemotherapy and 22 control subjects (six females, 16 males; mean age 50.1 years) with non-neoplastic lung diseases. RESULTS: No significant differences in sIL2R serum concentrations were observed at diagnosis between the control and LC group or when comparing the different histotypes, disease stages (IIIa-b vs IV) and survival (survival < or = 12 vs > 12 months). On comparing the sequential variations of the examined parameters a significant increase in sIL2R (P < 0.007) after 1 and 6 months versus basal value was observed only in patients surviving less than 12 months and in those who did not respond to chemotherapy. Moreover a negative correlation was observed between sIL2R serum concentrations and CD25+ and CD16+ lymphocyte subsets. Evaluation of survival curves of patients with basal sIL2R > or < or = 700 U/ml showed a slightly lower survival rate in the former group. CONCLUSIONS: The present results, confirming the poor utility of sIL2R in the diagnostic phase of the disease, show its usefulness in prognostic evaluation and in the clinical surveillance of patients with advanced lung cancer submitted to polychemotherapy. In this case any variations in sIL2R serum levels are likely to relate to the spread of the neoplasia rather than to the host immune response.     

Cyclosporin A and trifluoperazine, two resistance-modulating agents, increase ivermectin neurotoxicity in mice

The P-glycoprotein expressed in the blood-brain barrier has been associated with the restricted access of many compounds to the central nervous system. Mice lacking the mdr1a P-glycoprotein gene show an accumulation of various drugs in brain tissues. P-glycoprotein is also correlated with the phenomenon of multidrug resistance in tumour cells. To investigate the effects of drugs that modulate multidrug resistance in the selective permeability of the blood-brain barrier, mice were treated with cyclosporin A or trifluoperazine plus ivermectin, a P-glycoprotein substrate, that has a limited access to the central nervous system. When mice received an injection of cyclosporin A (50 mg/kg, intraperitoneally) or trifluoperazine (750 microg/kg, intraperitoneally) one hour prior to the administration of ivermectin (10-15 mg/kg, intraperitoneally) there was an increase in the acute toxicity of ivermectin. HPLC analysis of brain tissues indicated that the ivermectin brain concentration was 2.5 times higher when mice were previously treated with cyclosporin A (50 mg/kg). These results suggest that attention should be given to the side effects of drugs that interact with P-glycoprotein and are commonly used clinically and also to the possibility of creating a pharmacological gap in the blood-brain barrier that allows the access of chemotherapeutic drugs to brain tumours.     

Fluoxetine and fluvoxamine combined with individual cognitive-behaviour therapy in binge eating disorder: a one-year follow-up study

BACKGROUND: : The treatment of binge eating disorder (BED) is still the object of debate. In the present study, the effectiveness of antidepressant drugs (fluoxetine - FLX - 60 mg/day, fluvoxamine - FLV -300 mg/day), cognitive-behavioural therapy (CBT) and combined treatments (CBT + FLX, CBT + FLV) has been evaluated in a randomized, clinical trial. Results at the end of the active treatment (in the 24th week) and 1-year follow-up outcomes have been evaluated. METHODS: One hundred eight (44 M, 64 F) BED patients were randomly assigned to either CBT, FLX (60 mg/day), FLV (300 mg/day), CBT + FLX or CBT + FLV, for 24 weeks. At the beginning (T0), at the end (T1) of treatment and after 1 year (T2), body mass index (BMI) and eating attitude and behaviours (by EDE 12.0D) were assessed. RESULTS: At T1, BMI and EDE scores were significantly reduced in CBT, CBT + FLX and CBT + FLV, but not in the FLX and FLV treatment groups. In the CBT + FLV group, a greater (p < 0.05) reduction of EDE total scores was observed, when compared to CBT + FLX or CBT treatment groups. At T2, BMI was significantly higher than at T1, but still significantly lower than at T0 in the CBT, CBT + FLX and CBT + FLV groups, while EDE scores remained unchanged from T1 in all treatment groups. CONCLUSIONS: CBT was more effective than FLX or FLV in the treatment of BED. The addition of FLX to CBT does not seem to provide any clear advantage, while the addition of FLV could enhance the effects of CBT on eating behaviours. Modifications of eating behaviours are maintained at the 1-year follow-up, although the lost weight was partly regained.     

Heat treatment modifies the allergenicity of beef and bovine serum albumin

The effect of heat on the allergenicity of beef and bovine serum albumin was investigated among 10 toddlers skin prick test (SPT)-positive to raw and cooked beef. The meat-allergy diagnosis was confirmed during double-blind, placebo-controlled food challenge (DBPCFC) with 180 g of beef cooked for 5 min at 100°C. SPT with homogenized and freeze-dried beef, and heated and unheated bovine serum albumin were performed. Both heated and unheated bovine serum albumin, homogenized beef, and freeze-dried beef were used in trial DBPCFC. All children were SPT-positive to unheated bovine serum albumin. Seven were positive to heated bovine serum albumin, one to freeze-dried beef, and none to homogenized beef. DBPCFCs were negative for homogenized beef and freeze-dried beef, positive for unheated bovine serum albumin in five patients, and positive for heated albumin in four children. We conclude that heating reduces sensitization to beef and bovine serum albumin but does not abolish reactivity to albumin under home conditions. However, industrially heat-treated and sterilized homogenized beef and freeze-dried beef may be suitable substitutes in beef-allergic children's diets.     

Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2

Mutations in the TSC1 or TSC2 tumor suppressor genes lead to tuberous sclerosis complex (TSC), a dominant hamartomatous disorder that often presents with mental retardation, epilepsy and autism. The etiology of these neurological symptoms is unclear and the function of the TSC pathway in neurons is unknown. We found that in post-mitotic, hippocampal pyramidal neurons of mice and rats, loss of Tsc1 or Tsc2 triggered enlargement of somas and dendritic spines and altered the properties of glutamatergic synapses. Furthermore, loss of a single copy of the Tsc1 gene was sufficient to perturb dendritic spine structure. Morphological changes required regulation of the actin-depolymerization factor cofilin at a conserved LIM-kinase phosphorylation site, the phosphorylation of which was increased by loss of Tsc2. Thus, the TSC pathway regulates growth and synapse function in neurons, and perturbations of neuronal structure and function are likely to contribute to the pathogenesis of the neurological symptoms of TSC.     

A cis element in the recombination activating gene locus regulates gene expression by counteracting a distant silencer

We have identified a silencer and an antisilencing element that interact at a distance of 85 kilobases to regulate expression of the recombination activating genes Rag1 and Rag2 in thymocytes. Transgenic experiments showed that Rag promoter-proximal cis elements directed tissue-specific expression and that a Runx-dependent intergenic silencer suppressed expression in developing T cells. Deletion of the antisilencing element from the genomic Rag locus unmasked the intergenic silencer and abrogated Rag expression in developing CD4(+)CD8(+) T cells. We speculate that the Rag antisilencing element belongs to a class of cis elements that might be useful for genome diversification by activating genes encoded by otherwise silent transposable elements.