Charge and size selectivity of proteinuria in children with idiopathic nephrotic syndrome

 Experimental studies have pointed to charge selectivity as an important determinant of glomerular permeability to macromolecules. Loss of glomerular basement membrane (GBM) polyanion has been proposed as a cause of the selective proteinuria in minimal change nephrotic syndrome (MCNS). However, the presence of less-anionic albumin in urine than plasma from MCNS and focal and segmental glomerulosclerosis (FSGS) patients has been interpreted both as evidence for partial maintenance of charge selectivity and for involvement of other pathogenic mechanisms. The exact role of charge selectivity in the pathogenesis of nephrotic proteinuria remains controversial. We have examined the clearance of endogenous proteins of differing size and charge in children with idiopathic nephrotic syndrome (NS). Chromatofocusing was used to determine the isoelectric points (pIs) of albumins in paired plasma and urine samples from patients with FSGS (n = 6) and MCNS (n = 6). Charge selectivity was assessed by comparing the pIs of the fractions with the highest albumin concentration (modal pI) in plasma and urine. The difference between the modal pIs was defined as the delta modal pI. Charge selectivity was also assessed from the albumin/transferrin and IgG4/IgG1 clearance ratios; size selectivity from the IgG1/albumin and IgG1/transferrin as well as the IgG4/albumin and IgG4/transferrin clearances. In children with FSGS, the mean (± SD) delta modal pI was  – 0.05 ± 0.16, and in MCNS  – 0.05 ± 0.11. Neither value differed significantly from zero. The albumin/transferrin clearance ratio showed no significant difference between FSGS and MCNS, but the IgG4/IgG1 clearance ratio was significantly higher in MCNS (P<0.05). Size selectivity was significantly reduced in FSGS compared with MCNS (for IgG1/transferrin P<0.01 and for IgG1/albumin P<0.05). For IgG4/transferrin and IgG4/albumin, P was <0.05. In conclusion, there was no evidence for residual charge selectivity in idiopathic NS associated with either MCNS or FSGS during nephrotic-range proteinuria. There was a significant loss of GBM size selectivity in children with FSGS with heavy proteinuria compared with children with MCNS with heavy proteinuria. Received August 7, 1996; received in revised form and accepted December 16, 1996     

Antisense knockdown of the Shaker-like Kv1.1 gene abolishes the central stimulatory effects of amphetamines in mice and rats.

Amphetamine (AMPH) is an indirect sympathomimetic compound classified as a substrate-type releaser that distinguishes it from other stimulants that act as uptake 1 blockers, such as cocaine (COC). In mammals, AMPH elicits central stimulation, hypermotility, anorexia, analgesia and analeptic activity, mainly through the increase of extracellular brain dopamine (DA). The inversion of vesicular transporters and/or intravesicular alkalinization is assumed to have a role in AMPH-induced exocytosis. However, the action mechanism of this compound has not yet been completely clarified. Recent evidence on the action of AMPHs indicates potassium channel-blocking properties in peripheral tissues. We investigated the possible involvement of a Shaker-like Kv1.1 channel subtype in the central effects of AMPH, using an antisense oligodeoxyribonucleotide (aODN) that specifically and reversibly inhibits the expression of these channels in the brain. The effect of aODN pretreatments was studied by evaluating the modification of behavioral effects induced in mice through the intracerebroventricular administration of AMPH, COC, or other compounds. The aODN in mice almost completely blocked the stimulatory effects of AMPH and other releasers but was ineffective in reducing the central activity of COC. In aODN-pretreated rats a strong reduction of the AMPH, but not of the COC-stimulated DA efflux from nucleus accumbens was observed. Our results suggest that the stimulant effects of AMPH and chemically related compounds, but not COC, require the presence of functionally active Kv1.1 channels in the brain.     

Effects of long-term acetyl-L-carnitine administration in rats--II: Protection against the disrupting effect of stress on the acquisition of appetitive behavior.

Long-term acetyl-L-carnitine (ALCAR) administration prevents the development of escape deficit produced by acute exposure to unavoidable stress. However, it does not revert the escape deficit sustained by chronic stress exposure. Rats exposed to chronic stress show a low dopamine (DA) output in the nucleus accumbens shell (NAcS) and do not acquire an appetitive behavior sustained by the earning of vanilla sugar (VS) made contingent on the choice of one of the two divergent arms of a Y-maze (VS-sustained appetitive behavior, VAB), while control rats consistently do. The present study shows that ALCAR treatment in rats exposed to a 7-day stress protocol prevented a decrease in DA output in the NAcS and medial prefrontal cortex (mPFC) of rats, and that it strengthened the DA response to VS consummation in the same two areas. Moreover, rats treated with long-term ALCAR or exposed to chronic stress while treated with ALCAR acquired VAB as efficiently as control rats. Moreover, VAB acquisition in stressed rats treated with ALCAR coincided with the reversal of the deficits in escape and in dopaminergic transmission in the NAcS. Thus, repeated ALCAR treatment preserved the DA response to VS in chronically stressed rats and this effect appeared to be predictive of the rat's competence to acquire VAB.     

Natural killer cell activity and serum immunoglobulins in epileptic patients

Serum immunoglobulins and the activity of natural killer (NK) cells of 50 epileptic patients (eight with idiopathic generalized epilepsy and 42 with cryptogenic partial epilepsy) and 28 controls have been studied. The values of IgA, IgG and IgM were the same-in patients and controls. The NK activity in controls was linearly related to the effector-to-target ratio, but this linear relationship was not observed in epileptic patients. The cytotoxic activity of NK cells at the lowest effector-to-target ratio was significantly greater in patients than in controls. This increase was observed in each therapy group. Our results seem to confirm a disturbance of the immune system in epileptic patients and suggest that this modification of cellular immunity is not a drug effect but is related to the illness itself.     

Evaluation of the offer vs. serve option within self-serve, choice menu lunch program at the elementary school level

The feasibility of a centralized menu and the effectiveness of an "offer vs. serve" option within a self-serve, choice menu lunch program at the elementary school level were determined. Student trays (no. = 370/day) were visually evaluated for foods chosen and consumed. The same 1-week menu was served at two urban Southern schools. One represented a high-poverty-area, all-black-student school and the other represented a middle-income-area school with a white to black student ratio of 3:1. Students were able to choose the required USDA minimal number of three foods, and 66% of the foods selected were similar at the two schools, demonstrating that a centralized menu was feasible. Three-fourths of the students were able to choose more than 75% of one-third of the RDA for all nutrients except pyridoxine and ascorbic acid at both schools and iron at the high-poverty school. Twenty-five percent or more of the students did not consume 75% of one-third the Recommended Dietary Allowance for thiamin, vitamin B-6, ascorbic acid, iron, and magnesium at either school or of niacin and vitamin A at the middle-income school. Overall plate waste was 12.9%, with younger children wasting more food than older children and more waste in the middle-income than the high-poverty school. In general, the "offer vs. serve" was an effective option.     

Peripheral cytokine release in Alzheimer patients: correlation with disease severity

Various studies suggested that inflammation is involved in the pathogenesis of Alzheimer's disease (AD). We investigated cytokine release from LPS-stimulated blood cells of 32 AD patients, with different disease severity, compared to 16 age-related controls. A significant decrease of IL-1beta and IL-6 secretion was observed in severely demented patients; TNF-alpha release was also decreased, but not significantly. By contrast, mild and moderate patients showed a cytokine release similar to controls. IL-1beta, IL-6 and TNF-alpha secretion was negatively correlated with the severity of dementia, quantified by the MMSE. Our data suggest that alterations of the immune profile are associated with AD progression.     

TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma

A metastasizing mouse cell line (TS/A), originated from a mammary adenocarcinoma which arose spontaneously in a BALB/c female retired breeder, has been established in vitro. It displayed a remarkable morphologic heterogeneity, which is evident in plastic adherent cultures (cell types ranging from epithelial-like to fibroblast-like) as well as in semi-solid agar cultures. The TS/A line exhibited the presence of specific cytoplasmic estradiol receptor, with a binding activity of 16 fmoles/mg cytosol protein. The in vivo growth pattern was as follows: (1) a s.c. inoculum of 105 cells caused a 100 per cent tumor take and kill in syngeneic animals; mean survival time was 54 + 1 days; (2) it did not show significant transplant immunogenicity in syngeneic animals; (3) it was able to give rise to both spontaneous lung metastases and artificial lung colonies; (4) it had a high capacity to grow in H-2 matched, minor histocompatibility antigen incompatible hosts (106 cells killed 100 per cent DBA/2 mice in 58 + 2 days). This line of spontaneous mammary tumor cells is proposed as a useful model for studies on the heterogeneity of the neoplastic population in relation to metastatic spread, on tumor immunogenicity, and on therapy of mammary neoplasia.