A longitudinal examination of neuropsychological and clinical functioning in boys with attention deficit hyperactivity disorder (ADHD): improvements in executive functioning do not explain clinical improvement.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) often, but not always, persists into adulthood. Investigations of the associations between clinical and biological markers of persistence can shed light on causal pathways. It has been proposed that compensatory improvements in executive neuropsychological functioning are associated with clinical improvements. This is the first study to test this hypothesis prospectively. METHOD: The clinical and neuropsychological functioning of 17 boys with ADHD (mean age 10.45 years at time 1; 14.65 years at time 2) and 17 typically developing (TYP) boys (mean age 10.39 years at time 1; 14.47 years at time 2) was tested on two occasions, 4 years apart. This was done using a battery of standardized neuropsychological tests that included tasks with high and low executive demands. RESULTS: Clinical improvements were observed over time. Neuropsychological performance improvements were also evident, with ADHD boys developing with a similar pattern to TYP boys, but with a developmental lag. Whilst there was an association between reduced symptoms and superior performance at retest for one task with a high executive demand (spatial working memory), this was not seen with two further high executive demand tasks [Stockings of Cambridge and intra-dimensional extra-dimensional (ID/ED) set shifting]. Also, there was no association between change in executive functioning and change in symptoms. Baseline performance on the ID/ED set-shifting task predicted better clinical outcome. Only change in performance on the low executive demand delayed matching-to-sample task predicted better clinical outcome. CONCLUSIONS: These data highlight the importance of longitudinal measurements of cognition, symptoms and treatment response over time in children and adolescents with ADHD.

Hypoxia-inducible factor 1alpha is involved in the prostaglandin metabolism of osteoarthritic cartilage through up-regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes.

OBJECTIVE: To investigate crosslinks between catabolic and anabolic pathways in articular cartilage by examining the synthesis and distribution pattern of microsomal prostaglandin E synthase 1 (mPGES-1) in healthy and osteoarthritic (OA) cartilage and analyzing its functional relationship to hypoxia-inducible factor 1alpha (HIF-1alpha) in primary articular chondrocytes. METHODS: Normal cartilage and OA cartilage were subjected to immunohistochemical staining for mPGES-1 and HIF-1alpha. Isolated chondrocytes were cultivated under 21% or 1% O(2). Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction were used to detect genes differentially expressed in chondrocytes cultured under normoxic compared with hypoxic conditions. Immunoblotting was conducted to evaluate intracellular protein levels of mPGES and nuclear accumulation of HIF-1alpha under different oxygen tension levels and with different stimulatory or inhibitory chemical agents. RESULTS: We found enhanced levels of expression of the mPGES-1 gene and an increased number of OA chondrocytes showing staining for mPGES-1 in OA cartilage. Microarray analysis demonstrated that mPGES-1 was among the genes that were up-regulated to the greatest degree in primary chondrocytes exposed to 1% O(2). In vitro, hypoxia led to an enhanced synthesis of mPGES-1, coinciding with a nuclear accumulation of the transcription factor HIF-1alpha. In chondrocyte culture, stimulation with dimethyloxaloylglycine promoted the expression of mPGES-1, phosphoglycerate kinase 1, and cyclooxygenase 2 (COX-2) by stabilizing HIF-1alpha protein levels. A reduction of mPGES-1 synthesis was detected after treatment with 2-methoxyestradiol, correlating with lower HIF-1alpha activity. In contrast, synthesis of mPGES-1 was not influenced by treatment with the specific COX-2 inhibitor NS398. CONCLUSION: These findings suggest that the transcription factor HIF-1alpha is involved in the up-regulation of mPGES-1 and may therefore play an important role in the metabolism of OA cartilage.

Assimilate export by leaves of ricinus communis L. growing under normal and elevated carbon dioxide concentrations: the same rate during the day, a different rate at night

Castor bean (Ricinus communis L.) plants were grown for 5-7 weeks in a controlled environment at 350 &mgr;l l(-1) or 700 &mgr;l l(-1) CO(2). Carbon assimilation, assimilate deposition, dark respiration and assimilate mobilization were measured in leaves 2, 3 and 4 (counted from the base of the plant), and a balance sheet of carbon input and export was elaborated for both CO(2) concentrations. Carbon dioxide assimilation was nearly constant over the illumination period, with only a slight depression occurring at the end of the day in mature source leaves, not in young source leaves. Assimilation was ca. 40% higher at 700 &mgr;l l(-1) than at 350 &mgr;l l(-1) CO(2). The source leaves increased steadily in weight per unit area during the first 3 weeks, more at 700 &mgr;l l(-1) than at 350 &mgr;l l(-1) CO(2). On top of an irreversible weight increase, there was a large gain in dry weight during the day, which was reversed during the night. This reversible weight gain was constant over the life time of the leaf and ca. 80% higher at 700 &mgr;l l(-1) than at 350 &mgr;l l(-1). Most of it was due to carbohydrates. The carbon content (as a percentage) was not altered by the CO(2) treatment. Respiration was 25% higher in high-CO(2) plants when based on leaf area, but the same when based on dry weight. The rate of carbon export via the phloem was the same during the daytime in plants grown at 350 &mgr;l l(-1) and 700 &mgr;l l(-1) CO(2). During the night the low-CO(2) plants had only 50% of the daytime export rate, in contrast to the high-CO(2) plants which maintained the high export rate. It was concluded that the phloem loading system is saturated during the daytime in both CO(2) regimes, whereas during the night the assimilate supply is reduced in plants in the normal CO(2) concentration. Two-thirds of the carbon exported from the leaves was permanently incorporated as plant dry matter in the residual plant parts. This "assimilation efficiency" was the same for both CO(2) regimes. It is speculated that under 350 &mgr;l l(-1) CO(2) the growing Ricinus plant operates at sink limitation during the day and at source limitation during the night.

Transcription factor Egr-1 regulates glomerular mesangial cell proliferation.

Increase of glomerular mesangial cells (MCs) is a prominent histopathological finding in many types of glomerulonephritis. We have shown previously that expression of the zinc-finger transcription factor, early growth response gene-1 (egr-1), is closely correlated with the proliferation of cultured MCs. To elucidate whether Egr-1 is required for MC proliferation, we inhibited serum-induced Egr-1 expression by phosphothioate-modified antisense oligonucleotides (ODNs). Uptake of antisense ODNs into MCs was demonstrated, and five different egr-1 antisense ODNs were tested for their impact on serum-induced egr-1 mRNA and protein levels and on MC growth. The most potent egr-1 antisense ODN inhibited serum-induced egr-1 mRNA by 68%, protein induction by 58%, and MC replication as measured by [3H]thymidine uptake and cell counts by 78 and 46%, respectively. The effects of antisense ODNs on MC growth correlated closely with their ability to inhibit Egr-1 protein. ODNs acted in a dose-dependent manner, the minimal effective concentration being 1 microM. Control ODNs had no significant effects. In addition, antisense ODNs against egr-1 potently inhibited endothelin-1-induced Egr-1 expression and MC growth. Heparin, a known inhibitor of MC growth, suppressed serum-induced [3H]thymidine uptake by 39% and egr-1 mRNA expression by 44%. We conclude that Egr-1 is an essential part of the mitogenic signal transduction cascade in cultured MCs.