Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.     

Electrosensory interference in naturally occurring aggregates of a species of weakly electric fish, Eigenmannia virescens

The detection and identification of behaviorally relevant signals in the presence of competing signals in the environment is a major challenge of animal sensory systems. In weakly electric fish such as Eigenmannia virescens, the interactions between the autogenous electric field and the electric fields of nearby conspecifics can have profound effects on the perception of other behaviorally relevant electrosensory information. To better understand the natural signals that the nervous system of Eigenmannia experiences during the processing of electrosensory information, we examined the electrosensory milieu of Eigenmannia in the wild and in the laboratory. Recordings of the electric fields of Eigenmannia were made in 'black' and 'white' waters near the Napo River in eastern Ecuador. Fourier analysis revealed that Eigenmannia typically experience the electric fields of three to five conspecifics during the day and night in each habitat. The median difference in electric organ discharge frequencies between nearby Eigenmannia during the day was 23 Hz in black water habitats, 41 Hz in white water, and 37 Hz at night in both habitats: these signals are known to activate tuberous electroreceptors and downstream CNS circuits. There was no correlation between the number of individual Eigenmannia detected at recording sites and electric organ discharge frequencies. Further, Eigenmannia apparently do not maximize the frequency differences between conspecifics. In laboratory studies fish were preferentially observed in aggregates of two fish or more. Aggregate sizes observed in the laboratory were similar to those in the wild.     

Long-term effects of acute and of chronic hypoxia on behavior and on hippocampal histology in the developing brain

Ten-day-old rat pups (P10) subjected to acute hypoxia (down to 4% O2) had as adults increased aggression (handling test), memory impairment (water maze test), and decreased CA1 cell counts. Pups subjected to chronic hypoxia (10% O2 from P0 to P21) had increased aggression, hyperactivity (open-field test), and decreased CA1 cell counts. Chronic hypoxia with superimposed acute hypoxia resulted in consequences that were not different from those of chronic hypoxia.     

Effect of insulin and angiotensin II receptor subtype-1 antagonist on myocardial remodelling in rats with insulin-dependent diabetes mellitus

OBJECTIVES: To assess the role of insulin or an angiotensin II receptor antagonist (losartan), or both, in preventing cardiomyocyte damage in rats suffering from insulin-dependent diabetes mellitus (IDDM), and to correlate it with insulin receptor modulation at the cardiomyocyte, coronary endothelium and skeletal muscle cell level. DESIGN: Animals were divided into groups of normal rats, diabetic rats, and diabetic rats given insulin, each subdivided into a control group and an experimental group treated with losartan. METHODS: The animals were killed 1 month after enrollment to the study. Perfusion of the heart with iodine-125-labelled insulin was carried out for all the groups and the binding kinetics of insulin to its receptors on the coronary endothelial cells and the cardiomyocytes were determined using a physical/mathematical model. In addition, tissue samples from the heart and intercostal skeletal muscle were snap frozen and used for histological, indirect immunofluorescence and western blot analysis. RESULTS: Cardiac muscle from diabetic animals exhibited diffuse cardiomyopathic changes consisting of widespread vacuolation, loss of striation and cellular hypertrophy, which were reduced and even prevented by treatment with insulin and losartan. In addition, losartan seemed to mediate the upregulation of insulin receptor density on cardiomyocytes and skeletal muscle, and increase insulin receptor affinity at the coronary endothelial site. Finally, treatment with losartan induced a significant decrease in glucose concentrations in the diabetic group compared with the appropriate controls. CONCLUSIONS: Addition of losartan to the standard insulin treatment in non-hypertensive animals with IDDM offers new benefits concerning cardiac protection and prevention of damage. This may be attributed, in part, to insulin receptor density and sensitization.     

Relationship between percentage of VO2max and type of physical activity in obese and non-obese adolescents

AIM: The objective of the present study was to determine oxygen uptake (VO(2)) and percentage of maximum oxygen uptake (%VO2max) in obese and non-obese adolescents during various activities in standardised conditions, and the corresponding %VO2max in free-living conditions. METHODS: Twenty-seven obese and 50 non-obese adolescents aged 12 to 16 years participated in this study. Body composition was assessed by bioelectrical impedance analysis and dual energy X-ray absorptiometry (DXA), VO2max by treadmill tests, VO2 corresponding to various activities by whole body calorimetry, and time and % VO2max corresponding to various activities in free-living conditions using the heart-rate recording method and a physical activity diary. RESULTS: VO2max (l/min) was 27.4% higher in obese than in non-obese subjects (p<0.001), but not significantly different after adjustment for fat-free mass (FFM). In the whole body calorimeters, with the same activity program, % VO2max corresponding to sleep and sedentary activities were lower in obese than in non-obese girls (-15.1% and -12.3%, p<0.05), but not significantly different between obese and non-obese boys. However, walking at 4-5-6 km/h corresponded to 47-59% and 71% of VO2max, respectively, in obese, and 34-41% and 48% of VO2max in non-obese subjects (p<0.001). In free-living conditions, moderate physical activities and sports corresponded to 52% vs 35%, and 39% vs 51% of VO2max, respectively, in obese and non-obese adolescents. CONCLUSIONS: In standardised conditions %VO2max did not correspond to the same type of physical activity in obese compared to non-obese adolescents. Consequently, % VO2max is inadequate for comparing the types of physical activities of obese and non-obese adolescents in free-living conditions.     

Systemic treatment of cerebral cortex lesions in rats with a new secreted phospholipase A2 inhibitor

An internal fragment of the human neuroprotective polypeptide DSEP (Diffusible Survival Evasion Peptide) was delivered at 0.4 mg/kg (subcutaneously) 20-30 min after stab wound lesions in the parietal cortex of anesthetized rats. The peptide, CHEASAAQC or CHEC-9, inhibited the inflammatory response to the lesion and the degeneration of neurons adjacent to the wound. Four days after surgery, peptide-treated animals (n = 6) had 75% fewer reactive ameboid microglia/brain macrophages in the cortical parenchyma surrounding the lesion compared to vehicle-injected control rats (n = 6, p = 0.004). The cortical laminae in area 2 adjacent to the lesion were completely obscured in controls because of the increase in inflammatory cells and frank degeneration of neurons, while there was preservation of the neurons and cytoarchitecture after peptide treatment. In parallel experiments, CHEC-9 was found to inhibit the enzymatic activity of secreted phospholipase A2 (sPLA2), including activity present in the serum of peptide-injected rats. Kinetic analysis revealed the peptide increased the average Km for serum by 318% when tested 45 min after treatment (peptide-treated, n = 6; control-treated, n = 6; p = 0.0087), suggesting the principal effect of the peptide was to lower the affinity of serum sPLA2 for substrate. The sPLA2 inhibition by this particular peptide sequence appeared to be highly specific since inversion of a single pair of amino acids eliminated the inhibitory effect. Phorbol-12-myristate-13-acetate stimulated platelet aggregation, a PLA2-regulated activity, was also inhibited by the peptide. The discovery of CHEC-9 makes it possible to study in vivo the long appreciated contribution made by PLA2-directed inflammation to both acute and chronic neurodegeneration and may be helpful in designing therapies to limit neuron death in these conditions.     

External fixators in the treatment of fractures in children

New properties are being modified in the external fixator instrumentation that are leading to the more indicated use of this type of fixation especially in children's lower limb fractures. Dynamization, the ability to lengthen the limb and easy wound care are among the new properties of the monoplane external fixator, along with greater stability than older models. These new properties are now making the external fixator an indication rather than a choice in many cases. We have retrospectively studied 21 children with lower limb fractures treated by 28 external fixators. The results of this study show advantages such as lower infection rate, consolidation without the need of reoperation, easy physiotherapy, easy wound care and the ability to perform shortening and lengthening in the same set. Disadvantages are mostly complications that are due to the external fixation such as iatrogenic vascular lesions, pins tract infections and iatrogenic fractures.     

Basal cell nevus syndrome: guidelines for early detection

Basal cell nevus syndrome is an autosomal dominant condition with complete penetrance and variable expressivity. It is characterized by five major components, including multiple nevoid basal cell carcinomas, jaw cysts, congenital skeletal abnormalities, ectopic calcifications, and plantar or palmar pits. Other features include a host of benign tumors, ocular defects, and cleft lip and palate. Guidelines for diagnosis include a family history, careful oral and skin examinations, chest and skull radiographs, panoramic radiographs of the jaw, magnetic resonance imaging of the brain, and pelvic ultrasonography in women.     

Delivery by forceps: indications and materno-fetal morbidity

A retrospective study concerning patients having had a delivery by means pair of forceps over a period going from 1st Jun 1999 to 31st December 2000. The frequency of the use of forceps for delivery is 4.95%. The defect of eviction was an indication of the pair of forceps. Fetal suffering was the main indication. Maternal morbidity was represented essentially by a more or less injury of the genital tract with a rate of 11.1%. The rate of neonatal mortality is 1.28%. The maternal improvement of the maternal and fetal prognosis depends on an accurate indication of the use of forceps. In certain circumstances, mainly in fetal suffering, it is often difficult to choose between the high way and the low way.