Are there cognitive subtypes in adult attention deficit/hyperactivity disorder?

There has been increasing knowledge of the treatment, diagnosis, and demographics of adults with residual attention deficit/hyperactivity disorder (ADHD). However, less is known about the neuropsychological functioning in adults with residual ADHD. In comparing the clinical neuropsychological test performance of a group of adult clinic patients with residual ADHD (N = 30) with that of normal controls (N = 10), we found the patients performed worse on the Trail Making Test, a visual continuous performance test, and the "Brown-Peterson" Auditory Consonant Trigrams Test, but not on any other neuropsychological measures. This pattern indicated a deficit in the area of executive control type functioning, a functional deficit that could be linked to dysregulation of frontal lobe brain systems. Of equal interest was that patients diagnosed with ADHD/hyperactive impulsive type (ADHD+) and patients diagnosed with ADHD/inattentive type (ADHD-) had different types of executive system deficits. ADHD+ was associated with relative deficiency on the Wisconsin Card Sorting Test. ADHD- was associated with relative deficiency on the "Brown-Peterson" Auditory Consonant Trigrams Test, a measure of working memory, as well as less olfactory identification on a smell identification test. The data are discussed in terms of recent localization theories of frontal lobe function. The preliminary data suggest that the different cognitive weaknesses of ADD subtypes may be linked to dysregulation of separate frontal brain regions and/or neurotransmitter systems.     

Differential effects of inhibitors of cyclooxygenase (cyclooxygenase 1 and cyclooxygenase 2) in acute inflammation

The anti-inflammatory activity of drugs more selective for cyclooxgenase isoform inhibition (cyclooxygenase 1, cyclooxygenase 2), were compared in rat carrageenin-induced pleurisy. Suppression of inflammation by cyclooxygenase 2-selective inhibitors, NS-398 (N-[-2-cyclohexyloxy]-4-nitrophenyl methanesulphonamide) and nimesulide (4-nitro-2-phenoxy-methanesulfonanilide), and by piroxicam and aspirin, more selective for cyclooxygenase 1, was measured. Piroxicam and aspirin significantly inhibited inflammatory cell influx, exudate and prostaglandin E2 formation, 6 h after carrageenin injection. Cyclooxygenase 2 inhibitors had little effect on these parameters with NS-398 alone reducing prostaglandin E2 levels, but increasing levels of leukotriene B4. In contrast, at 3 h after carrageenin injection, cyclooxygenase 2 inhibitors significantly inhibited all inflammatory parameters however suppression with piroxicam and aspirin was greater, and more pronounced than at 6 h. NS-398 and nimesulide dosing did not reduce thromboxane B2 production from platelets isolated from rats with carrageenin-induced pleurisy, demonstrating that at the doses used, cyclooxygenase 2 inhibitors did not inhibit cyclooxygenase 1, as platelets contain only this isoform. Therefore, in the rat carrageenin-induced pleurisy, drugs more selective for the inhibition of cyclooxygenase 1 attenuate inflammation over a wider time frame than cyclooxygenase 2-selective drugs, suggesting a significant role for cyclooxygenase 1 in this model. Inhibition of cyclooxygenase 2 by NS-398 however, resulted in an increase in the potent chemoattractant leukotriene B4.     

An import signal in the cytosolic domain of the Neurospora mitochondrial outer membrane protein TOM22

TOM22 is an integral component of the preprotein translocase of the mitochondrial outer membrane (TOM complex). The protein is anchored to the lipid bilayer by a central trans-membrane segment, thereby exposing the amino-terminal domain to the cytosol and the carboxyl-terminal portion to the intermembrane space. Here, we describe the sequence requirements for the targeting and correct insertion of Neurospora TOM22 into the outer membrane. The orientation of the protein is not influenced by the charges flanking its trans-membrane segment, in contrast to observations regarding proteins of other membranes. In vitro import studies utilizing TOM22 preproteins harboring deletions or mutations in the cytosolic domain revealed that the combination of the trans-membrane segment and intermembrane space domain of TOM22 is not sufficient to direct import into the outer membrane. In contrast, a short segment of the cytosolic domain was found to be essential for the import and assembly of TOM22. This sequence, a novel internal import signal for the outer membrane, carries a net positive charge. A mutant TOM22 in which the charge of the import signal was altered to -1 was imported less efficiently than the wild-type protein. Our data indicate that TOM22 contains physically separate import and membrane anchor sequences.     

The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release

This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an IkappaB superrepressor, tumor necrosis factor alpha (TNFalpha) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFalpha induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFalpha treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFalpha treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFalpha-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing DeltaFADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFalpha, although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFalpha-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.     

Effects of hindlimb contraction on pressor and muscle interstitial metabolite responses in the cat

We used the microdialysis technique to measure the interstitial concentration of several putative metabolic stimulants of the exercise pressor reflex during 3- and 5-Hz twitch contractions in the decerebrate cat. The peak increases in heart rate and mean arterial pressure during contraction were 20 +/- 5 beats/min and 21 +/- 8 mmHg and 27 +/- 9 beats/min and 37 +/- 12 mmHg for the 3- and 5-Hz stimulation protocols, respectively. All variables returned to baseline after 10 min of recovery. Interstitial lactate rose (P < 0. 05) by 0.41 +/- 0.15 and 0.56 +/- 0.16 mM for the 3- and 5-Hz stimulation protocols, respectively, and were not statistically different from one another. Interstitial lactate levels remained above (P < 0.05) baseline during recovery in the 5-Hz group. Dialysate phosphate concentrations (corrected for shifts in probe recovery) rose with stimulation (P < 0.05) by 0.19 +/- 0.08 and 0.11 +/- 0.03 mM for the 3- and 5-Hz protocols. There were no differences between groups. The resting dialysate K+ concentrations for the 3- and 5-Hz conditions were 4.0 +/- 0.1 and 3.9 +/- 0.1 meq/l, respectively. During stimulation the dialysate K+ concentrations rose steadily for both conditions, and the increase from rest to stimulation (P < 0.05) was 0.57 +/- 0.19 and 0.81 +/- 0.06 meq/l for the 3- and 5-Hz conditions, respectively, with no differences between groups. Resting dialysate pH was 6.915 +/- 0.055 and 6.981 +/- 0.032 and rose to 7.013 (P < 0.05) and 7.053 (P < 0.05) for the 3- and 5-Hz conditions, respectively, and then became acidotic (6. 905, P < 0.05) during recovery (5 Hz only). This study represents the first time simultaneous measurements of multiple skeletal muscle interstitial metabolites and pressor responses to twitch contractions have been made in the cat. These data suggest that interstitial K+ and phosphate, but not lactate and H+, may contribute to the stimulation of thin fiber muscle afferents during contraction.     

A 32-bp deletion within the CCR5 locus protects against transmission of parenterally acquired human immunodeficiency virus but does not affect progression to AIDS-defining illness

The beta-chemokine receptor CCR5 is required as a coreceptor by non-syncytium-inducing (NSI) strains of human immunodeficiency virus type 1 (HIV-1). NSI viruses predominate early during an infection and are thought to be important for the transmission of HIV-1. The importance of CCR5 during parenteral transmission of HIV-1 was investigated. The distribution of the homozygous deleted CCR5 genotype among 566 exposed persons with hemophilia and 97 exposed transfusion recipients indicated that the lack of CCR5 expression protected persons from infection. This suggests that the initial predominance of NSI viruses during an infection does not result from limited availability of CXCR4-expressing cells within the mucosa but rather implies a more fundamental requisite for CCR5-expressing cells early during an infection regardless of the route of transmission. In addition, no difference in the rate of progression to AIDS (CDC 1987 definition) of infected heterozygous compared with homozygous wild type subjects was observed.     

Managing capital and administrative (indirect) costs to achieve strategic objectives: the dialysis clinic versus the outpatient clinic

During the race for costing accuracy in health care, managers should acknowledge the equal importance of interdepartmental relations. Although newer costing systems can produce more accurate numbers, greater costing accuracy may not always strengthen the organization. This article demonstrates that subsidizing some capital and administrative (indirect) costs for select hospital departments may help to achieve strategic management objectives.