The EEG Consistency Index as a Measure of ADHD and Responsiveness to Medication

The primary diagnostic procedure for Attention-Deficit/Hyperactivity Disorder (ADHD) is the clinical interview, because psychological, neuropsychological, and neurological tests to date have not had sufficient specificity. Currently, there is no objective means to measure severity of ADHD, or the extent to which it is benefited by various dosages of medication. We recently reported that a certain EEG profile, the Consistency Index, occurring during the transition between two easy cognitive tasks clearly differentiated ADHD from non-ADHD boys between the ages of 8 and 12. The current study replicated this with older males (19–25) using different tasks, and a double blind, placebo versus Ritalin® controlled crossover design. Seven ADHD subjects were found to have a significantly lower Consistency Index than 6 non-ADHD males while transitioning from 2 Simple tasks during placebo condition, while only the ADHD subjects demonstrated a significant improvement in their Consistency Index while on Ritalin®. Similar but nonsignificant trends were observed while transitioning across Hard tasks.     

Fetal rabbit pulmonary artery smooth muscle cell response to ryanodine is developmentally regulated

To study developmental changes in intracellular calcium handling in pulmonary artery smooth muscle cells (PASMCs), cells were isolated from distal and proximal pulmonary arteries from rabbits at different developmental stages: juvenile (4-6 wk old), newborn (<48 h), and full-term fetal. Isolated PASMCs were studied using the calcium-sensitive dye fura 2. Cells from each age group responded to caffeine with an increase in calcium; however, ryanodine (50 microM) only increased calcium in fetal distal PASMCs. The ryanodine-induced increase was due to influx of extracellular calcium because it was blocked by removal of extracellular calcium or by diltiazem. The calcium-sensitive potassium (K(Ca)) channel blocker iberiotoxin produced a transient increase in calcium in the fetal distal PASMCs, which could be inhibited by prior application of ryanodine. Conversely, the ryanodine response was inhibited if iberiotoxin was given first. With the use of electrophysiology and confocal microscopy, fetal PASMCs were shown to exhibit spontaneous transient outward currents and calcium sparks, respectively. These observations suggest that ryanodine-sensitive release of calcium from the sarcoplasmic reticulum and K(Ca) channels act together to control intracellular calcium only in fetal distal PASMCs.     

Histones and nucleosomes in Archaea and Eukarya: a comparative analysis

Archaeal histones from mesophilic, thermophilic, and hyperthermophilic members of the Euryarchaeota have primary sequences, the histone fold, tertiary structures, and dimer formation in common with the eukaryal nucleosome core histones H2A, H2B, H3, and H4. Archaeal histones form nucleoprotein complexes in vitro and in vivo, designated archaeal nucleosomes, that contain histone tetramers and protect approximately 60 base pairs of DNA from nuclease digestion. Based on the sequence and structural homologies and experimental data reviewed here, archaeal nucleosomes appear similar, and may be homologous in evolutionary terms and function, to the structure at the center of the eukaryal nucleosome formed by the histone (H3+H4)₂ tetramer. Received: January 22, 1998 / Accepted: February 16, 1998     

Alcohol/cholecystokinin-evoked pancreatic acinar basolateral exocytosis is mediated by protein kinase C alpha phosphorylation of Munc18c

The pancreatic acinus is the functional unit of the exocrine pancreas whose role is to secrete zymogens into the gut lumen for food digestion via apical exocytosis. We previously reported that supramaximal CCK induced apical blockade and redirected exocytosis to ectopic sites on the basolateral plasma membrane (BPM) of this polarized cell, leading to pancreatitis. Basolateral exocytosis was mediated by protein kinase C phosphorylation of BPM Munc18c, causing its displacement into the cytosol and activation of BPM-bound Syntaxin-4 to form a SNARE complex. To mimic the conditions of alcoholic pancreatitis, we now examined whether 20 mm alcohol followed by submaximal CCK might mimic supramaximal CCK in inducing these pathologic exocytotic events. We show that a non-secretory but clinically relevant alcohol concentration (20 mm) inhibited submaximal CCK (50 pM)-stimulated amylase secretion by blocking apical exocytosis and redirecting exocytosis to less efficient BPM, indeed mimicking supramaximal CCK (10 nM) stimulation. We further demonstrate that basolateral exocytosis caused by both stimulation protocols is mediated by PKC alpha-induced phosphorylation of Munc18c: 1) PKC alpha is activated, which binds and induces phosphorylation of PM-Munc18c at a Thr site, and these events can be inhibited by PKC alpha blockade; 2) PKC alpha inhibition blocks Munc18c displacement from the BPM; 3) PKC alpha inhibition prevents basolateral exocytosis but does not rescue apical exocytosis. We conclude that 20 mm alcohol/submaximal CCK as well supramaximal CCK stimulation can trigger pathologic basolateral exocytosis in pancreatic acinar cells via PKC alpha-mediated activation of Munc18c, which enables Syntaxin-4 to become receptive in forming a SNARE complex in the BPM; and we further postulate this to be an underlying mechanism contributing to alcoholic pancreatitis.     

Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption

In this study, we establish that the tyrosine kinase Syk is essential for osteoclast function in vitro and in vivo. Syk^−/− osteoclasts fail to organize their cytoskeleton, and, as such, their bone-resorptive capacity is arrested. This defect results in increased skeletal mass in Syk^−/− embryos and dampened basal and stimulated bone resorption in chimeric mice whose osteoclasts lack the kinase. The skeletal impact of Syk deficiency reflects diminished activity of the mature osteoclast and not impaired differentiation. Syk regulates bone resorption by its inclusion with the αvβ3 integrin and c-Src in a signaling complex, which is generated only when αvβ3 is activated. Upon integrin occupancy, c-Src phosphorylates Syk. αvβ3-induced phosphorylation of Syk and the latter's capacity to associate with c-Src is mediated by the immunoreceptor tyrosine-based activation motif (ITAM) proteins Dap12 and FcRγ. Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and αvβ3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target.     

The ageing mitochondrial genome

The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process. One plausible mechanism for ageing is accumulation of mutations in the mitochondrial genome. In this review, we discuss some of the most convincing data surrounding age-related mtDNA mutations and the evidence that these mutations contribute to the ageing process.     

Slowmo is required for Drosophila germline proliferation

Null mutations in the Drosophila gene, slowmo (slmo), result in reduced mobility and lethality in first-instar larvae. Slowmo encodes a mitochondrial protein of unknown function, as do the two other homologs found in Drosophila. Here, we have studied a hypomorphic P-element allele of slmo demonstrating its effects on germline divisions in both testes and ovaries. Using in situ studies, enhancer-trap activity, and promoter fusions, we have shown that slmo expression in testes is found in the somatic cyst cells (SCC). The hypomorphic allele for Slmo revealed apoptotic loss of germline cells in the larval germline, culminating in a complete absence of the germline in adult flies. In females, a similar degeneration of the germarium is observed, while reporter gene expression is found in both germline and somatic cells. Using a null mutation in female germline clones, we find slmo is dispensable from the germline cells. Our results suggest that Slowmo is not required in germline cells directly, but is required in SCCs responsible for maintaining germline survival in both sexes.     

Water and enzyme secretion are tightly coupled in pancreatic secretion stimulated by food or CCK-58 but not by CCK-8

Pancreatic secretion of protein, water, chloride, and bicarbonate under basal conditions and in response to intravenous and intraduodenal stimuli were studied in awake rats fully recovered from surgery. During the basal phase of pancreatic secretion, protein output and water output were weakly correlated or uncorrelated, consistent with separate regulation and distinct cellular origin of enzyme (acinar cells) and water (duct cells), referred to as the two-component paradigm of pancreatic secretion. When pancreatic secretion was stimulated physiologically, water and protein output abruptly became strongly and significantly correlated, suggesting that protein secretion and water secretion are tightly coupled or that protein secretion is dependent on water secretion. The apparent function of this coupling is to resist or prevent increases in protein concentration as protein output increases. This pattern of secretion was reproduced by intravenous infusion of the CCK-58 form of cholecystokinin, which strongly stimulates pancreatic water and chloride secretion, but not by CCK-8, which only weakly stimulates water and chloride secretion in a non-dose-dependent manner. The remarkably tight association of water and protein secretion in food-stimulated and CCK-58-stimulated pancreatic secretion is consistent with a single cell type as the origin of both water and enzyme secretion, i.e., the acinar cell, and is not consistent with the two-component paradigm of pancreatic secretion. Because CCK-58 is the only detectable endocrine form of cholecystokinin in the rat and its bioactivity pattern is markedly and qualitatively different from CCK-8, actions previously recorded for CCK-8 should be reexamined.