Academic task persistence of normally achieving ADHD and control boys: performance, self-evaluations, and attributions.

The authors examined academic task persistence, pretask expectancies, self-evaluations, and attributions of boys with attention-deficit/hyperactivity disorder (ADHD) as compared with control boys. Participants were 83 ADHD boys and 66 control boys, all normally achieving. Prior to the task, performance expectancies were assessed. After a success-failure manipulation with find-a-word puzzles, performance on subsequent trials, self-evaluations, and attributions were evaluated. Compared with controls, ADHD boys solved fewer test puzzles, quit working more often, and found fewer words on a generalization task. Consistent with these behavioral findings, research assistants rated ADHD boys as less effortful and less cooperative than control boys. Although ADHD boys did not differ significantly from controls in their posttask self-evaluations, they did differ significantly from controls in some aspects of their attributions. Attributional data indicated that ADHD boys endorsed luck as a reason for success more strongly and lack of effort as a reason for failure less strongly than controls.

Transporters on demand: intrahepatic pools of canalicular ATP binding cassette transporters in rat liver.

ABC transporter trafficking in rat liver induced by cAMP or taurocholate and [(35)S]methionine metabolic labeling followed by subcellular fractionation were used to identify and characterize intrahepatic pools of ABC transporters. ABC transporter trafficking induced by cAMP or taurocholate is a physiologic response to a temporal demand for increased bile secretion. Administration of cAMP or taurocholate to rats increased amounts of SPGP, MDR1, and MDR2 in the bile canalicular membrane by 3-fold; these effects abated after 6 h and were insensitive to prior treatment of rats with cycloheximide. Half-lives of ABC transporters were 5 days, which suggests cycling of ABC transporters between canalicular membrane and intrahepatic sites before degradation. In vivo [(35)S]methionine labeling of rats followed by immunoprecipitation of (sister of P-glycoprotein) (SPGP) from subcellular liver fractions revealed a steady state distribution after 20 h of SPGP between canalicular membrane and a combined endosomal fraction. After mobilization of transporters from intrahepatic sites with cAMP or taurocholate, a significant increase in the amount of ABC transporters in canalicular membrane vesicles was observed, whereas the decrease in the combined endosomal fraction remained below detection limits in Western blots. This observation is in accordance with relatively large intracellular ABC transporter pools compared with the amount present in the bile canalicular membrane. Furthermore, trafficking of newly synthesized SPGP through intrahepatic sites was accelerated by additional administration of cAMP but not by taurocholate, indicating two distinct intrahepatic pools. Our data indicate that ABC transporters cycle between the bile canaliculus and at least two large intrahepatic ABC transporter pools, one of which is mobilized to the canalicular membrane by cAMP and the other, by taurocholate. In parallel to regulation of other membrane transporters, we propose that the "cAMP-pool" in hepatocytes corresponds to a recycling endosome, whereas recruitment from the "taurocholate-pool" involves a hepatocyte-specific mechanism.

Regulation of sorbitol efflux in different renal medullary cells: similarities and diversities.

It is well accepted that organic osmolytes, including sorbitol, play a major role in the volume regulation of renal medullary cells. The signal leading to an activation of release channels during RVD is, however, poorly understood. Hypotonicity induced sorbitol efflux was investigated in freshly isolated rat inner medullary collecting duct (IMCD) cells and in rabbit medullary thick ascending limb of Henle's loop (TALH) cells biochemically or using labeled sorbitol. The time course of release was compared with changes in cell volume, measured by confocal microscopy, and alterations in cell calcium (Ca(i)) determined by Fura 2 technology. In IMCD cells sorbitol release, volume decrease and Ca(i) transients show a close temporal correlation. In addition increases in Ca(i) without volume changes stimulate sorbitol efflux. In TALH cells sorbitol release starts after a significant lag time and reaches a maximum when cell volume is already partially restored. The same discrepancy is observed with regard to changes in Ca(i) and sorbitol efflux. These studies suggest that in IMCD cells changes in Ca(i) are the main regulator for the sorbitol permeability of the plasma membrane. The sorbitol channel present in TALH cells seems to operate predominantly independently of Ca(i). Despite this diversity in signal transduction the sorbitol channels in both renal cell types appear, however, not to be stretch-activated.

Intracellular trafficking and regulation of canalicular ATP-binding cassette transporters.

The bile canaliculus contains at least four ATP-binding cassette (ABC) proteins responsible for ATP-dependent transport of bile acids (spgp), nonbile acid organic anions (mrp2), organic cations (mdr1), and phosphatidylcholine (mdr2). Other ABC transporters (including mrp3) have also been partially localized to the canaliculus; however, their function has not been fully delineated. The specific amount and function of spgp and mrp2 in the canalicular membrane increases in response to taurocholate and cAMP. The mechanism involves increased recruitment of spgp and mrp2 from Golgi to the canalicular membrane by a microtubular and PI3 kinase-dependent vesicular trafficking system. Because the effects of taurocholate and cAMP summate, two distinct pathways are proposed. Mdr family members traffic either directly to the apical plasma membrane or, in the case of spgp, through a separate intracellular pool(s); in either case, there is no direct evidence for transcytosis of ABC transporters from Golgi to basolateral plasma membrane and subsequently to the canalicular plasma membrane. Direct transfer from Golgi to apical membrane was demonstrated by in vivo pulse labeling, in vitro membrane localization, and on-line video microscopy in WIFB9 cells that were stably transfected with mdr1-GFP. A critical role for 3'-phosphoinositide products of PI3 kinase was demonstrated in the intracellular trafficking of canalicular ABC transporters and for optimal transporter activity within the canalicular membrane. These studies suggest that many intracellular components, including ATP, Ca2+, numerous GTPases, microtubules, cytoplasmic motors, and other unknown factors, are required for physiologic regulation of ABC transporter traffic from Golgi to the canalicular membrane. Defects in this complex system are postulated to produce an "intrahepatic traffic jam" that results in defective ABC transporter function in the canalicular membrane and, consequently, in cholestasis.

Newly synthesized canalicular ABC transporters are directly targeted from the Golgi to the hepatocyte apical domain in rat liver.

Newly synthesized canalicular ectoenzymes and a cell adhesion molecule (cCAM105) have been shown to traffic from the Golgi to the basolateral plasma membrane, from where they transcytose to the apical bile canalicular domain. It has been proposed that all canalicular proteins are targeted via this indirect route in hepatocytes. We studied the membrane targeting of rat canalicular proteins by in vivo [(35)S]methionine metabolic labeling followed by preparation of highly purified Golgi membranes and canalicular (CMVs) and sinusoidal/basolateral (SMVs) membrane vesicles and subsequent immunoprecipitation. In particular, we compared membrane targeting of newly synthesized canalicular ABC (ATP-binding cassette) transporters MDR1, MDR2, and SPGP (sister of P-glycoprotein) with that of cCAM105. Significant differences were observed in metabolic pulse-chase labeling experiments with regard to membrane targeting of these apical proteins. After a chase time of 15 min, cCAM105 appeared exclusively in SMVs, peaked at 1 h, and progressively declined thereafter. In CMVs, cCAM105 was first detected after 1 h and subsequently increased for 3 h. This findings confirm the transcytotic targeting of cCAM105 reported in earlier studies. In contrast, at no time point investigated were MDR1, MDR2, and SPGP detected in SMVs. In CMVs, MDR1 and MDR2 appeared after 30 min, whereas SPGP appeared after 2 h of labeling. In Golgi membranes, each of the ABC transporters peaked at 30 min and was virtually absent thereafter. These data suggest rapid, direct targeting of newly synthesized MDR1 and MDR2 from the Golgi to the bile canaliculus and transient sequestering of SPGP in an intracellular pool en route from the Golgi to the apical plasma membrane. This study provides biochemical evidence for direct targeting of newly synthesized apical ABC transporters from the Golgi to the bile canaliculus in vivo.

Generalization of behavioral and psychostimulant treatment of attention-deficit/hyperactivity disorder (ADHD): discussion and examples.

Assessment and treatment of attention-deficit/hyperactivity disorder (ADHD) are reviewed in order to highlight the importance of examining individual differences in treatment response. It is emphasized that treatment response in children often varies as a function of the domain measured, the setting evaluated, and intensity of the treatment. Three case studies are presented to illustrate this point. The first case study is an example of a child who showed a consistent response to medication across settings and domains and treatment intensities. The second case study is an example of a child who showed differential treatment response as a function of setting and/or treatment intensity, but was consistent across domain. The third case study is an example of a child who showed a differential response to treatment as a function of domain, but was consistent across settings and treatment intensities. These case studies highlight the need for systematic, comprehensive, individualized treatments for children with ADHD.

Validity of DSM-IV attention-deficit/hyperactivity disorder for younger children.

OBJECTIVE: Little is known about the validity of the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in young children. Moreover, the results of the DSM-IV field trials raised concerns that inclusion of the new predominantly hyperactive-impulsive type of ADHD in DSM-IV might increase the likelihood of the diagnosis being given to active but unimpaired preschool and primary school children. METHOD: The validity of DSM-IV criteria for each subtype of ADHD was evaluated in 126 children, aged 4 through 6 years, and 126 matched comparison children. Probands and controls were classified by using structured diagnostic interviews of the parent and a DSM-IV checklist completed by the teacher. RESULTS: Children who met DSM-IV criteria for each subtype of ADHD according to parent and teacher reports differed consistently from controls on a wide range of measures of social and academic impairment, even when other types of psychopathology and other potential confounds were controlled. CONCLUSIONS: When diagnosed by means of a structured diagnostic protocol, all three DSM-IV subtypes of ADHD are valid for 4- through 6-year-old children in the sense of identifying children with lower mean scores on measures of adaptive functioning that are independently associated with ADHD.

Characteristics of renal Na(+)-D-glucose cotransport in the skate (Raja erinacea) and shark (Squalus acanthias).

We have investigated the properties of the skate (Raja erinacea) and shark (Squalus acanthias) kidney Na(+)-D-glucose cotransporters (SGLT) in uptake studies of radiolabeled substrates into isolated renal brush-border membrane vesicles (BBMV). Scatchard plot analysis of the substrate dependence revealed that the Na(+)-D-glucose cotransporter population is homogenous within each species. Skate BBMV showed a relatively high affinity for D-glucose [Michaelis constant (K(m)) = 0.12 mM] with an apparent coupling ratio of approximately 2 Na+ to 1 D-glucose, whereas the shark transporter was much lower in affinity (K(m) = 1.90 mM) and had a lower coupling ratio, more like 1 Na+ to 1 D-glucose. These characteristics resemble the properties of SGLT1 and SGLT2, which are known to coexist in the mammalian kidney. Inhibitor studies using sugar analogs and glucosides suggested structural differences of the D-glucose binding site among these transporters, whereas the hydrophobic transporter domains in the vicinity of the D-glucose binding site appeared to be similar. In the high-affinity skate system, D-glucose was recognized by hydrogen bonds to the hydroxy groups at C-2, C-3, and C-4 and by hydrophobic interaction with the C-6 methylene group. In contrast, the low-affinity shark system seemed to lack the hydrophobic recognition motif for the C-6 methylene group of D-glucose.

Synthesis of the photoaffinity label [1'-14C]-6C-(azimethyl)octylglucoside and its reaction with isolated renal brush border membranes.

We describe the synthesis of the photolabile analog of n-octylglucoside (OG), 6C-(azimethyl)octylglucoside (diazirino-octylglucoside, DOG). This diazirino derivative (lambda max = 335 nm) can be activated with long-wavelength UV to generate a highly reactive carbene, an intermediate suitable for a covalent ligand-receptor linkage. In inhibitor studies on D-glucose uptake into rabbit renal brush border membrane vesicles (BBMV) DOG showed a competitive inhibition with regard to D-glucose with a Ki of 20 +/- 5 microM, which was not significantly different from that of the template compound OG (Ki = 30 +/- 10 microM). On irradiation (lambda max = 350 nm) of BBMV in the presence of [14C]DOG, proteins of 61, 72 to 78, and 95 kDa were labeled by photoinduction. A band of 73 kDa was also positive in Western blots using an anti-Na+/D-glucose cotransporter antibody. Further investigations revealed that the labeled proteins were presumably mainly glucosidases known to be present in high concentration in renal BBMV. By comparison with authentic material one of the labeled proteins (61 kDa) was identified as trehalase (EC 3.2.1.28). These studies suggest that labels such as DOG carrying the reactive group directly at the D-glucose moiety of the molecule can be used to label proteins with carbohydrate recognition sites.

Interactions of alkylglucosides with the renal sodium/D-glucose cotransporter.

To study the nature of the glucose binding pocket of the renal Na+/D-glucose cotransporter, we have evaluated the inhibitory potency of various alkylglucosides (AG) on sodium-dependent D-glucose uptake into hog kidney brush border membrane vesicles (BBMV). Inhibition at 0.1 mM AG level was found to be strongly dependent on the anomeric configuration, on the length and on the flexibility of the side chain. Beta-n-AG inhibited transport significantly more effectively compared to the corresponding alpha-anomer (n-octylglucoside: alpha-anomer 15%, beta-anomer 84%) and AG with an unsaturated n-alkenyl side chain were significantly less effective inhibitors than the corresponding saturated compound (cis/trans 3-n-beta-hexenylglucoside 53% and 32%, beta-n-hexylglucoside 76%). A series of beta-n-AG increasing in side chain length from 1 to 13 carbon atoms revealed a global maximum in the inhibition pattern when beta-AG with side chains ranging from 8 to 11 carbon atoms were used, thus beta-methylglucoside inhibited glucose transport by 13%, beta-n-nonylglucoside by 92%, and beta-n-tridecylglucoside showed no effect. Kinetic analysis of inhibition by beta-n-octylglucoside revealed a fully competitive type of inhibition with an apparent K(i) of 10 +/- 2 microM. n-Octylglucoside at 0.1 mM did not inhibit sodium-dependent L-alanine uptake; similarly, n-octylmannoside at 0.1 mM level did not affect D-glucose uptake. These results suggest that the inhibition of sodium-dependent D-glucose uptake was, at least in the concentration range tested (up to 0.1 mM), not due to a detergent effect of AG, but due to interaction with the carrier. Optimum interaction requires a beta-anomer with a glycosidic bond that places the alkyl chain into an equatorial position with regard to the D-glucose molecule and the two main determinants of the sugar recognition site C2 and C3. In addition, the alkyl chain has to be highly flexible. The alkyl chains thus apparently interact with hydrophobic sites at the carrier in a slightly coiled conformation, thereby AG with a chain length up to 6 carbon atoms interact only with one hydrophobic site, AG with higher chain length probably with two sites.

Epidemiologic observations of operating room infections resulting from variations in ventilation and temperature.

Over a period of years the ventilation system of a community hospital progressively deteriorated until it no longer met regulatory guidelines. The hospital, a publicly funded military facility, requested funding to repair the ventilation system, but funds were not forthcoming because of budget austerity. When an increase in infections was documented, high-risk operations were curtailed and funding was expedited. With the new improved ventilation system the operating rooms once again met regulatory guidelines and infections returned to baseline rates. Throughout the period infections remained below recognized national levels.

Correlates of alcoholic beverage preference: traits of persons who choose wine, liquor or beer.

We studied correlates of wine, hard liquor or beer preference among 53,172 white men and women in a Northern California prepaid health plan. Preference for a beverage type was reported by 51% of drinkers; 22% of persons with a preference reported exclusive use of the preferred beverage. Persons who prefer wine are likely to be women, temperate, young or middle-aged, non-smokers, better educated and free of symptoms or risk of illness. Persons who prefer liquor are likely to be men, heavier drinkers, middle-aged or older, less educated and afflicted with symptoms or risk factors for major illnesses. Persons who prefer beer are likely to be young men who are intermediate between wine and liquor preferrers for most traits. The traits of persons reporting exclusive use of a beverage type were similar. These data identify correlates of beverage choice which need to be controlled for in alcohol-health studies.

The leukocyte count: associations with intensity of smoking and persistence of effect after quitting.

Information from examinations of 62,541 adults enrolled in a study of smoking from 1979 through 1982 in Oakland, California, was used to explore the associations of various measures of intensity of smoking with the leukocyte count and to try to determine whether there was a persistent effect of smoking cigarettes on the leukocyte count. In current, regular cigarette smokers, leukocyte counts were higher in smokers of a large number of cigarettes and were associated with smoking cigarettes with a high tar and nicotine yield, deep inhalation of the cigarette smoke, and a longer duration of smoking. There was an association of past smoking with a high leukocyte count independent of age, sex, and race. In past smokers of cigarettes who used no other form of tobacco, the leukocyte count was related to time since quitting, smokers who had quit more recently having higher leukocyte counts. The study shows that a high leukocyte count is associated consistently with various measures of intensity of cigarette smoking. Moreover, it appears that smoking has an effect on the leukocyte count that persists after quitting. Delineation of the physiologic basis for the acute and chronic effects of cigarette smoking on the leukocyte count might lead eventually to a better understanding of the mechanisms for regulation of granulopoiesis and the release and destruction of leukocytes.

Vasectomy and the incidence of hospitalized illness.

To determine the long-term effects of vasectomy on health we studied the incidence of hospitalized illness in 4,385 vasectomized and 13,155 age and race-matched nonvasectomized men. In none of the 16 disease groupings we examined was the incidence of hospitalized illness in the vasectomized men significantly different from that in the nonvasectomized men, considering men with all durations of vasectomy. Neither the incidence of acute myocardial infarction, other ischemic heart disease nor that of all atherosclerotic diseases considered as a group was significantly different between the vasectomized and nonvasectomized men, even in those whose duration of vasectomy was 10 years or more. These data are reassuring, providing no evidence for an adverse health effect of vasectomy in men.

PIP: To determine the longterm effects of vasectomy on health, the incidence of hospitalized illness in 4385 men who had been vasectomized and 13,155 age- and race-matched men who had not undergone a vasectomy were studied. For the study subjects information on all hospitalizations in the medical care program's Northern California hospitals after the examination and through 1980 was obtained from computer stored discharge summaries, which were coded according to the International Classification of Diseases. Only the principal discharge diagnosis for each hospitalization was used in this analysis. The ratio of the incidence rate in the vasectomized men to the incidence rate in the controls was used to estimate relative risk. 95% confidence intervals for the relative risk estimates were calculated using the test based method. For all of the disease groupings, except neoplasms of unspecified nature, relative risk estimates were near 1. Considering men with all durations of vasectomy, for all of the disease groupings, the 95% confidence intervals for the estimated relative risk included 1 and, therefore, are not statistically significant. For all of the disease groupings the relative risk estimates were close to 1 in men with short and with long durations of vasectomy. The relative risks of acute myocardial infarction, other ischemic heart disease, and all atherosclerotic disease considered as a group were close to 1, and the confidence intervals were narrow. In men whose duration of vasectomy was greater than 10 years the relative risks of these diseases were near 1 and the confidence intervals for the relative risk estimates were narrow. In an earlier study it was found that the prevalence of peptic ulcer disease, kidney and bladder infection, joint swelling or pain, and back trouble was higher in vasectomized men. The incidence of hospitalized illnesses that are the counterpart of these conditions was low in this study, and the 95% confidence intervals were correspondingly wide. Thus the study is not an adequate examination of the relation of vasectomy to these conditions. In sum, the study provides no evidence for an adverse health effect of vasectomy in men.

A survey of personal habits, symptoms of illness, and histories of disease in man with and without vasectomies.

Using questionnaire information provided by 4.385 vasectomized and 13,155 matched, non-vasectomized men, we found no significant differences between them for a large number of symptoms and diseases, including those of the cardiovascular system. After taking into account differences in their martial status, past smoking habits, and physical activity at work, significant statistical associations of vasectomy with joint pain or swelling, back trouble, and a history of kidney or bladder infection persisted. Our data are inconsistent with the occurrence of large increases in the risks of many important diseases in vasectomized humans.

Physiologic measures in men with and without vasectomies.

PIP: Blood pressure, hematologic and blood chemistry measurements, and serologic tests for syphilis were performed on 4385 vasectomized and 13,155 age- and race-matched, nonvasectomized men who had multiphasic health checkups as members of a large prepaid medical care program in California. The study was carried out from 1977 through 1980. Age distributions of the vasectomized and nonvasectomized men were identical, 33% of both groups being 40 years old or younger, 33% being 41-50, and 34% being 51 or older. 37% of the vasectomized men had their vasectomies 10 or more years before their examination. Systolic blood pressure was slightly but significantly lower and potassium was slightly but significantly higher in the vasectomized group. All other differences were small and not biologically important. These data agree with other studies of vasectomized humans, in which no association of vasectomy with adverse health outcomes, including atherosclerosis, has been found.^ieng