Search

Cognitive functioning, particularly executive functioning, is a strong predictor of functional outcomes in people with schizophrenia. Cognitive remediation has been shown to improve specific cognitive processes, but adjunctive interventions are required for meaningful gains in adaptive functioning, particularly in people with chronic illness. This study examined whether (and how) environmental adaptations, used without training, may circumvent cognitive difficulties and facilitate everyday task performance in individuals with chronic schizophrenia. Forty-two individuals with chronic schizophrenia/schizoaffective disorder were administered cognitive measures and two versions of the Naturalistic Action Test (NAT)—a standard version (ST-NAT), and a user-centered version (UC-NAT) that incorporated environmental adaptations designed to facilitate task performance. The NAT conditions were counterbalanced across participants. Analyses compared performance between the NAT versions and examined the cognitive correlates of each NAT condition. Individuals with schizophrenia made fewer errors on the UC-NAT as compared to the ST-NAT; this between-group difference was significant for all error types. Compared to the ST-NAT, the UC-NAT performance was not significantly associated with an executive function measure of planning. Environmental adaptations may be implemented without extensive training to improve everyday action in individuals with chronic schizophrenia. Environmental adaptations that reduce planning demands may be most effective in this population. (JINS, 2015, 21, 319–329)

Planning of everyday tasks was examined in 48 inpatients with schizophrenia and 26 healthy controls. Participants were administered the Naturalistic Action Test, which requires completion of three everyday tasks (e.g., make toast and coffee). Planning variables, including planning behaviours (e.g., gathering items before engaging in a subtask) and planning time (e.g., period between task instructions and first action) were coded to evaluate forward thinking in these tasks. Results showed that planning variables were reliably coded. Controls demonstrated more planning behaviours than participants with schizophrenia; however, this difference was accounted for by education. People with schizophrenia spent significantly less time planning when planning time was analysed as a proportion of the total time on tasks. Planning variables were related to the ability to accomplish everyday task steps and to perform everyday task steps accurately. Together these findings suggest that rehabilitation strategies that emphasise both planning time and planning behaviours may facilitate everyday functioning in people with schizophrenia.

UGT enzymes catalyze the formation of glucuronic acid conjugates. Specifically selected representative stable isotope (C(13), N(15)) labeled peptide internal standards of each enzyme were employed to quantify UGTs 1A1 and 1A6 by LC-MS/MS using isotope dilution techniques. Inter day variability (n=5) for human liver microsomes wasor= 8.0 % for UGT1A1 andor= 19 % for UGT1A6. Comparison within a human liver microsomal library showed a strong correlation with Western blot for UGT1A1 concentrations (r=0.988). The data presented indicates that an accurate and reproducible method for UGT absolute quantification can be established using LC-MS/MS analysis of characteristic peptides within the protein.

Relative to our understanding of the memory and language deficits associated with Alzheimer's disease (AD), little is known about problems with everyday action performance (i.e., meal preparation, grooming). The resource theory proposes that everyday action problems are best explained by a unitary deficit in general cognitive resources. However, recent research suggests that omission and commission errors may reflect dissociable aspects of action impairment, with only omissions associated with resource limitations. This study examined everyday action performance in 70 participants with AD who also underwent a neuropsychological evaluation. First, correlation and principal component analyses were performed to examine the construct(s) that might explain everyday action impairment. Second, relations between everyday task component(s) and neuropsychological tests were examined by using correlation and regression analyses. Third, differences in everyday action error patterns were examined among participants of comparable overall impairment levels. Results showed omission and commission errors were uncorrelated and distinct components of everyday action performance, predicted by different neuropsychological tests, and differentially distributed even among participants with comparable overall impairment.

Neuropsychologists often recommend that patients with dementia and their caregivers use environmental adaptations to improve everyday functioning. Although these recommendations are intuitive (e.g., reduce clutter), most have never been experimentally tested. This study examined whether and how environmental adaptations improved everyday action in Alzheimer's disease (AD). Forty-six outpatients completed the Naturalistic Action Test (NAT; M. F. Schwartz, L. J. Buxbaum, M. Ferraro, T. Veramonti, & M. Segal, 2003), which requires completion of 3 everyday tasks. The NAT was administered under 2 conditions: standard and user centered. The standard NAT followed the procedures of the manual; object placement was standardized, but objects were not meaningfully arranged on the tabletop. In the user-centered NAT, objects were arranged in the order needed in the task, and a visual cue to monitor performance was placed on the table. These conditions were counterbalanced across participants. The user-centered condition improved performance on all NAT items and reduced commission and omission error rates. However, post hoc examination of commission error types showed improvement of substitution and off-task errors but no difference in anticipation and perseveration errors. Thus, environmental adaptations improved everyday performance in AD by facilitating task accomplishment, object selection, and task-congruent actions.

Life-threatening diarrhea afflicts a considerable percentage of patients treated with irinotecan, an anticancer agent with effects elicited through its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The primary detoxification pathway for SN-38 is glucuronidation. The purpose of this study was to evaluate the role that intestinal UDP-glucuronosyltransferases (UGTs) have from hepatic UGTs in modulating this diarrhea. To investigate this, Gunn rats devoid of UGT1A activity were injected with recombinant adenoviral vectors expressing UGT1A1, 1A6, and 1A7, resulting in reconstituted hepatic UGT expression comparable to a heterozygote. Hepatic microsome studies indicated that 4 to 7 days after adenoviral injection, transfected Gunn rats (j/jAV) had SN-38 glucuronide (SN-38G) formation rates three times higher than control heterozygote rats (j+AV). The adenovirus did not impart any glucuronidating capacity to the intestine in j/jAV rats, whereas j+AV rats possessed intestinal UGT function. After the administration of 20 mg/kg/day irinotecan i.p. to j/jAV rats 4 days after adenovirus injection, diarrhea ensued before the fourth irinotecan dose. j+AV rats were spared the diarrhea, and the toxicity was mild compared with the j/jAV rats, as measured by diarrhea scores, weight loss, and histological assessments of the cecum and colon. The pharmacokinetics of irinotecan, SN-38, and SN-38G indicate that the systemic exposure of SN-38 and SN-38G was higher and lower, respectively, in j/jAV rats. Despite this, the biliary excretion of irinotecan and metabolites was similar. Because intestinal UGTs are the main discriminating factor between j/jAV and j+AV rats, their presence seems to be critical for the gastrointestinal protection observed in j+AV rats.

Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p0.001) compared with rat liver microsomes. MPA UGT activities were reduced80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.

Prior research using performance-based assessment of functional impairment has informed a novel neuropsychological model of everyday action impairment in dementia in which omission errors (i.e., failure to complete task steps) dissociate from commission errors (i.e., inaccurate performance of task steps) and have unique neuropsychological correlates. However, this model has not been tested in other populations. The present study examined whether this model extends to schizophrenia. Fifty-four individuals with schizophrenia or schizoaffective disorder were administered a neuropsychological protocol and the Naturalistic Action Test (NAT), a performance-based measure of everyday action. A principal component analysis (PCA) was performed to examine the construct(s) comprising everyday action impairment, and correlations between the resultant component(s) and neuropsychological tests were examined. Results showed that omissions and a subset of commissions were distinct components of everyday action. However, results did not support unique associations between these components and specific neuropsychological measures. These findings extend the omission-commission model to schizophrenia and may have important implications for efficient assessment and effective rehabilitation of functional impairment, such as the potential efficacy of targeted interventions for the rehabilitation of omission and commission deficits in everyday functioning. Larger studies with prospective designs are needed to replicate the present preliminary findings. (JINS, 2014, 20, 1–10)

In Crigler-Najjar type II patients and, recently, in Crigler-Najjar type I patients treated with human hepatocyte cell therapy, phenobarbital has been used for reducing the serum bilirubin load. Its effect is attributed to induction of the enzyme required for hepatic bilirubin elimination, UDP-glucuronosyltransferase, UGT1A1. This study investigated the expression and inducibility of UGT1A1 in human donor livers and their corresponding primary hepatocyte cultures. Immunoblot analysis using a specific antibody directed against the amino terminal of the human UGT1A1 isoform showed that 5 hepatocyte donors exhibited a >50-fold difference in UGT1A1 level. UGT1A1 protein level correlated strongly with both liver microsomal bilirubin UGT activity and liver UGT1A1 mRNA level (r(2) =.82 and.72, respectively). Of the 4 patients with the lowest UGT1A1 levels, 3 were homozygotes for the UGT1A1 promoter variant sequence associated with Gilbert's syndrome, and the fourth was a heterozygote. The 3 donors with the highest levels had a history of phenytoin exposure. Hepatocytes isolated from the phenytoin-exposed donors exhibited marked declines in UGT1A1 mRNA levels during culturing. Induction studies using hepatocytes treated for 48 hours with phenobarbital (2 mmol/L), oltipraz (50 micromol/L), or 3-methylcholanthrene (2.5 micromol/L) revealed UGT1A1-inducing effects of phenobarbital, oltipraz, and, in particular, 3-methylcholanthrene. Our data suggest that both genetic and environmental factors play an important role in the marked interindividual variability in UGT1A1 expression. An understanding of these mechanisms could lead to advances in the pharmacological therapy of life-threatening unconjugated hyperbilirubinemia.

Previous work has shown that polycyclic aromatic hydrocarbons and oltipraz both induce an unidentified rat liver UDP-glucuronosyltransferase with activity toward benzo(a)pyrene-7, 8-diol, the proximate carcinogenic form of benzo(a)pyrene. Here we report the isolation of a benzo(a)pyrene-7,8-diol transferase-encoding cDNA, LC14, from an adult rat hepatocyte-derived cell line (RALA255-10G LCS-3). The predicted amino acid sequence of LC14 is nearly identical (5 differences out of 531 residues) to that deduced from UGT1A7, recently cloned at the genomic DNA level (Emi, Y., Ikushiro, S., and Kyanagi, T. (1995) J. Biochem. (Tokyo) 117, 392-399). Northern analysis of RNA from female F344 rat liver and LCS-3 cells revealed over a 40-fold and 4.4-fold enhancement by oltipraz treatment, respectively. Benzo(a)pyrene-7, 8-diol glucuronidating activity was detected (0.4 nmol/10(6) cells/16 h) in AHH-1 cells transfected with the LC14 expression vector, pMF6-LC14-3. The LC14-encoded transferase exhibited even higher activity toward certain benzo(a)pyrene phenols, including the major 3- and 9-phenol metabolites (4.1 and 2.8 nmol/10(6) cells/16 h, respectively). The Km of the enzyme for (-)-trans benzo(a)pyrene-7, 8-diol and 3-OH-BP was 15.5 and 12.3 microM, respectively. Northern analyses of total RNA revealed expression of LC14 or LC14-like RNA in all extrahepatic tissues tested. Marked inducibility by oltipraz was observed only in liver and (to a lesser extent) intestine. The results suggest that induction of UGT1A7 may explain the increased glucuronidating activities toward benzo(a)pyrene-7,8-diol and other metabolites that occur following treatment with polycyclic aromatic hydrocarbon-type inducing agents and oltipraz. UGT1A7 appears to represent an important cellular chemoprotective enzyme which mediates conjugation and elimination of toxic benzo(a)pyrene metabolites.

Executive function (EF) deficits in schizophrenia (SZ) are well documented, although much less is known about patterns of EF deficits and their association to differential impairments in everyday functioning. The present study empirically defined SZ groups based on measures of various EF abilities and then compared these EF groups on everyday action errors. Participants (n = 45) completed various subtests from the Delis-Kaplan Executive Function System (D-KEFS) and the Naturalistic Action Test (NAT), a performance-based measure of everyday action that yields scores reflecting total errors and a range of different error types (e.g., omission, perseveration). Results of a latent class analysis revealed three distinct EF groups, characterized by (a) multiple EF deficits, (b) relatively spared EF, and (c) perseverative responding. Follow-up analyses revealed that the classes differed significantly on NAT total errors, total commission errors, and total perseveration errors; the two classes with EF impairment performed comparably on the NAT but performed worse than the class with relatively spared EF. In sum, people with SZ demonstrate variable patterns of EF deficits, and distinct aspects of these EF deficit patterns (i.e., poor mental control abilities) may be associated with everyday functioning capabilities.

It has been shown that transesophageal echocardiography (TEE) is useful in evaluating atheromatous disease of the aortic arch and that such disease is a risk factor for stroke in medical patients. Data obtained by traditional methods of evaluating the aortic arch prior to cardiac surgery, namely, chest x-ray (CXR) and cardiac catheterization (CATH), were compared with that detected by TEE. Images of the descending thoracic aorta and aortic arch seen on intraoperative TEE in 258 cardiac surgical patients were graded as I = normal, II = intimal thickening or plaques

The ability of delta 9-Tetrahydrocannabinol (delta 9-THC) to modulate adenylate cyclase activity in mouse spleen cells was investigated. These studies were prompted by the recent identification and cloning of a G-protein coupled cannabinoid receptor localized in certain regions of the brain and the potential for a common mechanism between cannabinoid-mediated CNS effects and immunosuppression. Temporal addition studies were initially performed to identify the period of time when spleen cells in culture were most susceptible to the inhibitory effects of delta 9-THC, as measured by the day 5 IgM antibody forming cell response. delta 9-THC was only inhibitory when added to spleen cell cultures during the first 2 hr following antigen sensitization. In light of this time course, adenylate cyclase activity was measured in spleen cells incubated in the presence of 22 microM delta 9-THC for 5 min and subsequently stimulated with forskolin. delta 9-THC treated spleen cells demonstrated a 33% inhibition and a 66% inhibition in intracellular cAMP after a 5 or 15 min stimulation with forskolin, respectively. These studies suggest that inhibition of immune function by delta 9-THC may be mediated through the inhibition of intracellular cAMP early after antigen stimulation.

Although often incidentally found, diverticular disease of the small bowel and duodenum may generate complications and impose surgical treatment. Diagnosis of small bowel diverticulosis is difficult because the clinical picture is usually ambiguous. We report a case of diverticulosis of the whole intestine including a giant symptomatic retro-pancreatic duodenal diverticulum in a 74-year-old patient who presented with recurrent episodes of abdominal pain, weight loss and intestinal obstruction. The diagnosis was made by MRI enteroclysis and endoscopy. Open diverticulectomy with choledochostomy and insertion of a T-tube was performed and resulted in a rapid improvement of the symptoms.

Directly measured food intake in 31 overweight female smokers to test whether (a) calorie and carbohydrate intakes increase after smoking cessation and (b) double-blind d-fenfluramine (30 mg), a serotonin-releasing drug, suppresses weight gain, overeating, and dysphoric mood associated with stopping smoking. Placebo-treated patients grew dysphoric after smoking withdrawal and ate 300 kcal/day more from 2 to 28 days after, showing a 3.5-lb weight gain. Fat and protein intakes did not change, but carbohydrate intake increased (30% to 40%). D-fenfluramine prevented postcessation dysphoria. Although drug-treated patients ate more carbohydrate snacks just after quitting, they returned to baseline by 4 weeks, showing a 1.8-lb weight loss. Agents that enhance brain serotonin-mediated neurotransmission may help prevent weight gain, overeating, and dysphoric mood after smoking withdrawal.

Everyday action is impaired among individuals with schizophrenia, yet few studies have characterized the nature of this deficit using performance-based measures. This study examined the performance of 20 individuals with schizophrenia or schizoaffective disorder on the Naturalistic Action Test (M. F. Schwartz, L. J. Buxbaum, M. Ferraro, T. Veramonti, & M. Segal, 2003). Performance was coded to examine overall impairment, task accomplishment, and error patterns and was compared with that of healthy controls (n = 28) and individuals with mild dementia (n = 23). Additionally, 2 competing accounts of everyday action deficits, the resource theory and an executive account, were evaluated. When compared with controls, the participants with schizophrenia demonstrated impaired performance. Relative to dementia patients, participants with schizophrenia obtained higher accomplishment scores but committed comparable rates of errors. Moreover, distributions of error types for the 2 groups differed, with the participants with schizophrenia demonstrating greater proportions of errors associated with executive dysfunction. This is the 1st study to show different Naturalistic Action Test performance patterns between 2 neurologically impaired populations. The distinct performance pattern demonstrated by individuals with schizophrenia reflects specific deficits in executive function.

This study was designed to determine whether ambulatory electrocardiography in patients with recent stroke would lead to a change in clinical management or outcome and to express these findings in terms of cost benefit. A prospective, consecutive sample of patients (n = 100) with recent stroke referred from the neurology or medical services for ambulatory electrocardiography was identified. Ambulatory electrocardiograms were reviewed to identify patients with potentially important bradyarrhythmias, tachyarrhythmias, or atrial fibrillation. Patients were then followed up without interference with ongoing care to determine whether these findings led to changes in clinical management that might influence patient outcome. Of the 100 patients, 16 had an index "important" arrhythmia. No significant bradyarrhythmias were noted. Nonsustained ventricular tachycardia (or = 6 complexes) in two patients and supraventricular tachycardia (or = 10 complexes) in seven patients did not lead to management changes. Four patients had a history of atrial fibrillation who were in sinus rhythm; anticoagulation had been addressed in three; the fourth patient died before the issue could be addressed. Of three patients in atrial fibrillation, there was a history of atrial fibrillation and a decision regarding anticoagulation in each before monitoring. The cost of these 100 ambulatory electrocardiograms was about $55,000. In conclusion, these findings do not support the routine use of ambulatory electrocardiography in the evaluation of patients with stroke.

Short-term benefits have been demonstrated for laparoscopic-assisted colectomy. However, minimally invasive surgery is still in an evolutionary phase. In demonstrating that robotic devices also are useful in laparoscopic colonie surgery, it is fundamental to prove that a single surgeon can perform almost the entire operation on his own. METHODS: A single surgeon performed forty-one, laparoscopic-assisted, colorectal resections with the assistance of a robotic device (Automated Endoscopie System for Optimal Positioning, Computer MotionTM) maneuvering the laparoscope. A surgical assistant was included only for the open part of the operation. Main outcome measures were conversion rate, total operating time, and percentage of assistance by a second surgeon. RESULTS: There were no intraoperative complications, one case of conversion to open surgery, and three postoperative complications. The total operating time ranged from 126 to 252 minutes. A single surgeon with the assistance of a robotic device was able to perform approximately 70 percent of an ileocecal resection, 70 percent of a right hemicolectomy, 80 percent of a sigmoid resection, and 85 percent of a anterior rectal resection without further help of a surgeon. CONCLUSIONS: A single surgeon with the assistance of a computerized robotic system can complete at least two-thirds of a laparoscopic-assisted, colorectal resection on his own. The use of a robotic device in laparoscopic-assisted, colonie surgery is safe, efficient, and feasible, and will proven even more so in future. This also will result in a patient-driven demand for high-standard, minimally invasive surgery.

Background: The magnitude of surgical trauma after laparoscopic and open colonic resection was evaluated by examining postoperative serum values of interleukin-6 (IL-6), IL-10, C-reactive protein (CRP), and granulocyte elastase (GE) for further evidence of the benefit realized with minimally invasive approaches in colonic surgery. Methods: Altogether, 42 patients with Crohn's disease (n = 20) or colon carcinomas/adenomas (n = 22) were matched by age, gender, body mass index (BMI), and Crohn's Disease Activity Index for either a laparoscopic (n = 21) or an open colonic resection (n = 21). In both groups the postoperative serum levels of IL-6, IL-10, C-RP, and granulocyte elastase were determined, as indicators of surgical stress. Results: Laparoscopic and open colonic resection caused a significant increase in serum IL-6, IL-10, CRP, and granulocyle elastase levels. The comparison between laparoscopic and open colonic resections, however, showed significantly lower serum IL-6, IL-10, CRP, and granulocyte elastase levels after laparoscopic colonic resection, which was most evident for IL-6 and granulocyte elastase. Conclusions: Our study demonstrated that IL-6 and granulocyte elastase may be appropriated particularly to monitor surgical stress. By using these parameters, we found a significant reduction in surgical trauma after laparoscopic surgery, was compared with the open procedure. This supports the clinical findings of a clear benefit for patients undergoing laparoscopic colonic surgery.

One of the most important mechanisms involved in host defense against xenobiotic chemicals and endogenous toxins is the glucuronidation catalysed by UDP-glucuronosyltransferase enzymes (UGT). The role of genetic factors in determining variable rates of glucuronidation is not well understood, but phenotypic evidence in support of such variation has been reported. In the present study, six single nucleotide polymorphisms were discovered in the first exon of the UGT1A7 gene, which codes for the putative substrate-binding domain, revealing a high structural heterogeneity at the UGT1 gene locus. The new UGT1A7 proteins differ in their primary structure at amino acid positions 129, 131 and 208, creating four distinct UGT1A7 allelic variants in the human population: UGT1A7*1 (N129 R131 W208), *2 (K129 K131 W208), *3 (K129 K131 R208), and *4 (N129 R131 R208). In functional studies, HEK cells stably transfected to express the four allelic UGT1A7 variants exhibited significant differences in catalytic activity towards 3-, 7-, and 9-hydroxy-benzo(a)pyrene. UGT1A7*3 exhibited a 5.8-fold lower relative Vmax compared to wild-type *1, whereas *2 and *4 had a 2.6- and 2.8-fold lower relative Vmax than *1, respectively, suggesting that these mutations confer slow glucuronidation phenotype. Kinetic characterization suggested that these differences were primarily attributable to altered Vmax. Additionally, it suggested that each amino acid substitutions can independently affect the UGT1A7 catalytic activity, and that their effects are additive. The expression pattern of UGT1A7 studied herein and its catalytic activity profile suggest a possible role of UGT1A7 in the detoxification and elimination of carcinogenic products in lung. A population study demonstrated that a considerable proportion of the population (15.3%) was found homozygous for the low activity allele containing all three missense mutations, UGT1A7*3. These findings suggest that further studies are needed to investigate the impact of the low UGT1A7 conjugator genotype on individual susceptibility to chemical-induced diseases and responses to therapeutic drugs.

We report here that rats possess a hitherto unrecognized xenobiotic-inducible hepatic 7,8-dihydro-7,8-diol-benzo[a]pyrene (BPD) UDP-glucuronosyltransferase (UGT) activity. BPD UGT activity is induced in female F344 rat liver by treatment with the selective Phase 2 conjugation enzyme inducer oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione at 75-450 mg/kg per day for 3 days] and also by a polycyclic aromatic hydrocarbon-type inducer, beta-naphthoflavone (80 mg/kg per day for 3 days). Incubations of oltipraz-treated rat liver microsomes with racemic trans BPD (100 microM) resulted in formation of two fluorescent glucuronides that were resolved by silica thin layer chromatography (Rf 0.5 and 0.6). Incubations with either the (-) or (+) trans BPD isomers resulted in selective formation of the Rf 0.5 [designated -DS, for (-) diol specific] or Rf 0.6 [designated +DS, for (+) diol specific] glucuronide, respectively. The -DS and +DS BPD glucuronides were fluorescent under long wave ultraviolet irradiation, dependent on the presence of UDP-glucuronic acid in the incubation, and were beta-glucuronidase-sensitive. The inducing effect of oltipraz on BPD UGT activity was dose-dependent. The mean BPD UGT activity of the vehicle-treated control group was 0.05 +/- 0.02 nmol/mg per min compared with 0.53 +/- 0.07 nmol/mg per min in the group treated with oltipraz (450 mg/kg per day for 3 days) (P < 0.001). The apparent Km of the induced BPD UGT for BPD was 20 microM, suggesting that the enzyme has the capacity to bind and turnover BPD under physiological conditions. Pretreatment with beta-naphthoflavone, but not phenobarbital, induced BPD UGT activity to approximately the same extent as oltipraz. Neither oltipraz nor beta-naphthoflavone exhibited induction of BPD UGT in livers of homozygous Gunn rats, which lack functional UGT1-encoded isozymes. We conclude that the oltipraz- and polycyclic hydrocarbonresponsive BPD UGT is a member of the UGT1 family. The role of this isoform as a modifier of susceptibility to carcinogenesis elicited by B[a]P remains to be determined.

This study evaluated the current clinical use and costs of ambulatory electrocardiographic (AECG) monitoring for arrhythmia detection based on a cost per management decision analysis.Consecutive inpatient and outpatient 24-hour AECGs (n = 650) performed during the calendar year 1991 were retrospectively reviewed for clinical indication, arrhythmia detection, diary information, and whether a management decision that might alter patient outcome was derived from the data. The cost per management decision (based on a representative reimbursement of $550 per AECG) and the cost index (CI) (all tests divided by useful tests) were calculated.Although arrhythmias were identified in 91% of the patients, management decisions were indicated in only 18% (cost per decision, $2974; CI = 5.4). Management decisions were most often derived from the data in patients being evaluated for arrhythmia therapy (37 of 37 patients; cost per decision, $550; CI = 1). Symptoms and arrhythmias were correlated in only 11 patients (2%). More often typical clinical symptoms were present (26 patients) in the absence of an arrhythmia. Of 101 AECGs following a cerebrovascular event, four had unsuspected atrial fibrillation (cost per decision, $13,888; CI = 25.0). Dizziness or lightheadedness associated with other cardiac symptoms was more likely to lead to a management decision than the same symptoms in isolation (29% vs 7%; P.05). No patient had central nervous system symptoms correlated with an arrhythmia during the recording period or unsuspected ventricular tachycardia.Ambulatory electrocardiography has a highly variable and indication-dependent effectiveness and cost. The results suggest a strategy for improving the use of AECG based on knowing what testing indications are more likely to lead to useful clinical information.

In conclusion, TTM appears more effective than ambulatory ECG for the detection of arrhythmias associated with intermittent central nervous system or cardiac symptoms. Limiting TTM to patients with primarily cardiac symptoms and to a 1-week time period would have optimized cost-effectiveness in this group of patients.

Cannabinoid compounds, including the major psychoactive component of marihuana, delta 9-tetrahydrocannabinol (delta 9-THC), have been widely established as being inhibitory on a broad array of humoral and cell-mediated immune responses. The presence of cannabinoid receptors has been identified recently on mouse spleen cells, which possess structural and functional characteristics similar to those of the G-protein coupled cannabinoid receptor originally identified in rat brain. These findings, together with those demonstrating that delta 9-THC inhibits adenylate cyclase in splenocytes, strongly suggest that certain aspects of immune inhibition by cannabinoids may be mediated through a cannabinoid receptor-associated mechanism. The objective of the present studies was to determine whether inhibition of adenylate cyclase is relevant to mouse spleen cell immune function and, if so, whether this inhibition is mediated through a Gi-protein coupled mechanism as previously described in neuronal tissue. Spleen cell activation by the phorbol ester phorbol-12-myristate-13-acetate (PMA), plus the calcium ionophore ionomycin, produced a rapid but transient increase in cytosolic cAMP, which was inhibited completely by immunosuppressive concentrations of delta 9-THC (22 microM) and the synthetic bicyclic cannabinoid CP-55940 (5.2 microM), which produced no effect on cell viability. Inhibition by cannabinoids of lymphocyte proliferative responses to PMA plus ionomycin and sheep erythrocyte (sRBC) IgM antibody-forming cell (AFC) response, was abrogated completely by low concentrations of dibutyryl-cAMP (10-100 microM). Inhibition of the sRBC AFC response by both delta 9-THC (22 microM) and CP-55940 (5.2 microM) was also abrogated by preincubation of splenocytes for 24 hr with pertussis toxin (0.1-100 ng/mL). Pertussis toxin pretreatment of spleen cells was also found to directly abrogate cannabinoid inhibition of adenylate cyclase, as measured by forskolin-stimulated accumulation of intracellular cAMP. These results indicate that inhibition of the sRBC AFC response by cannabinoids is mediated, at least in part, by inhibition of adenylate cyclase through a pertussis toxin-sensitive Gi-protein coupled cannabinoid receptor. Additionally, these studies further support the premise that cAMP is an important mediator of lymphocyte activation.

Under phase I of an FDA-approved Investigational Device Exemption (IDE), six patients at the University of California, San Francisco (UCSF) have been implanted with the Clarion, a new multichannel, multiprogrammable cochlear implant system. Over a period of 5 years, the Clarion has been collaboratively developed by UCSF, the Research Triangle Institute (RTI) of North Carolina, and the device manufacturer and sponsor, MiniMed Technologies of Sylmar, California. For UCSF, it represents the culmination of 21 years of cochlear implant research. The Clarion incorporates the 16-contact electrode array developed at UCSF. This electrode is designed with a gentle curve and an elastic memory that allow it to hug the modiolar wall of the scala tympani. In addition, the electrode has mechanical features that prevent it from rotating upward and injuring the basilar membrane. One of the innovations necessary to allow broad clinical application of this device has been the development of an electrode insertion tool to assist the surgeon in safe placement. In each of the six UCSF cases, the insertion tool was used and electrode placement was achieved with ease. With the availability of a variety of speech processing strategies, the Clarion has also provided the opportunity for all of the patients tested to date to achieve some degree of open-set, auditory-only speech recognition. Surgical considerations and preliminary audiologic data demonstrate that the design rationale and objectives of the Clarion have been met.

The etiology and pathogenesis of ganglion cysts have not yet been completely illucidated. After surgical intervention there are recurrence rates of more than 30% described in the literature. Out of 425 operated patients a total of 348 patients could be reexamined. Recurrence rates as well as pre- and postoperative complaints are discussed.

Mitral valve prolapse is more prevalent in patients with autoimmune diffuse toxic goiter, suggesting a possible etiologic association. The prevalence of mitral valve prolapse was determined in 75 patients with chronic lymphocytic thyroiditis, another autoimmune thyroid disorder, and in 50 healthy control subjects. Mitral valve prolapse was found in 31 of 75 (41%) patients with chronic lymphocytic thyroiditis and in 4 of 50 (8%) controls (odds ratio, 8.10; 95% confidence interval, 2.64 to 24.83; p less than 0.0005). The age-race adjusted odds ratio was 9.26 (95% confidence interval, 2.83 to 30.26; p less than 0.0005). No correlation between the prevalence of mitral valve prolapse and the presence of hypothyroidism, serum antithyroid antibodies, or the duration of chronic lymphocytic thyroiditis was found. The prevalence of mitral valve prolapse is substantially increased in patients with the autoimmune thyroid disorders.

Aspirin induces ulceration, cellular exfoliation, and blood loss associated with decreases in gastric mucosal potential difference (PD). Certain prostaglandins prevent the development of experimental gastric and duodenal ulcers and modify indices related to ulceration. Misoprostol, a synthetic PGE1 derivative with gastric antisecretory and mucosal protective activities, was examined at gastric antisecretory doses in dogs with Heidenhain pouches, to determine its effect on aspirin-associated changes in PD, K+ efflux, blood loss, and cell shedding, as measured by DNA release. These parameters were examined before, during, and up to 4 hours after exposure of the pouches to aspirin. Disruption of the gastric mucosal barrier (GMB) by aspirin was associated with a fall in PD and losses of K+, DNA, and blood into the pouches. Misoprostol inhibited the fall in PD and prevented blood loss over the entire period examined. Cell loss was inhibited only during the recovery period immediately following aspirin. The effect of misoprostol on GMB is consistent with studies in which prostaglandins preserve the GMB and prevent necrotic ulcerations while allowing superficial cell damage.

Advances in technology regarding cochlear implantation and electroacoustic stimulation of the inner ears of deaf children has created cautious enthusiasm. The safety of cochlear implantation is now reasonably well established and language performance measures made over time are encouraging. When coupled with an effective (re)habilitation program, the cochlear implant promises to favorably influence the potential of deafened children.

Seven of 21 refractory depressed patients responded within 7 days to combined thyroid hormone-antidepressant treatment. Five of the 7 responders revealed evidence of subclinical hypothyroidism, suggesting that this subpopulation of depressed patients may benefit most from adjunctive thyroid hormone.

Clinical trials with the University of California, San Francisco (UCSF)/Storz multichannel cochlear implant began in February 1985. A total of 16 patients were implanted with this four channel unit, a vocoder-based, compressed-analog system. Twelve of the 16 patients have had their 1-year postoperative evaluations, which permitted observations of their performance over time. Of these 12 patients, 10 (83%) are able to obtain a considerable degree of speech recognition. This represents the achievement of some level of auditory-only understanding in a very high proportion of the implant population. Results are measured with a battery of speech reception tests, including monosyllabic word recognition (the standard clinical "speech discrimination" list), the recognition of key words in sentences, and connected discourse tracking. Conventional audiologic test procedures are used. The objective of the clinical trial was to evaluate the strategies developed by the UCSF implant team through neurophysiologic, histopathologic, and psychophysical investigations over the past 18 years. The UCSF/Storz trials have helped to clarify and to define the specifications for our next generation implant, an electrically transparent eight (bipolar) or 16 (monopolar) channel system.

Clinical trials of the UCSF/Storz multichannel cochlear implant were initiated in February 1985, under the sponsorship of Storz Instrument Company. This four-channel device uses simultaneous bipolar, radial stimulation and a vocoder-based speech processing scheme. To date, eighteen patients have been implanted with the UCSF/Storz implant at four clinical centers in the United States. Based on data accumulated through June 1986, fifteen of these patients had received their speech processors and were given at least an initial evaluation of their performance with the implant. Results have been very encouraging, with all but two of these patients obtaining some degree of open-set auditory-only speech recognition. Most patients have demonstrated improvement over time without extensive rehabilitative intervention and all patients have attained an enhancement in lip-reading ability, as measured with a tracking procedure. According to a self-rated performance scale, all patients have experienced improvement in general communicative function since receiving the implant.

Isolated canine parietal cells were used to study the ability of misoprostol to inhibit acid secretion in the presence of a number of acid secretagogues. Misoprostol inhibited histamine-stimulated acid secretion in a dose-dependent and noncompetitive manner. A concentration of 2-3 X 10(-9) M misoprostol inhibited maximal histamine-stimulated acid secretion by one half. Misoprostol had little to no effect on acid secretion stimulated by carbachol and dibutyryl cAMP, had no effect on the acid secretion directly stimulated by pentagastrin, and only modestly inhibited acid secretion stimulated by forskolin. Misoprostol noncompetitively inhibited cAMP formation in response to histamine, with an IC50 value similar to that for the inhibition of histamine-stimulated acid secretion. These results indicate that: (1) misoprostol specifically inhibits histamine-stimulated acid secretion in parietal cells, and (2) the antisecretory action of misoprostol is closely related to the reduction of histamine-stimulated cAMP formation with the site of major action most likely in the coupling process between histamine H2 receptor sites and histamine-sensitive adenylate cyclase.

Using a four-channel implant system with a vocoder-based processor developed at UCSF over an extensive period of research, clinical trials of the UCSF/Storz device were initiated in February 1985 under the sponsorship of Storz Instrument Company. To date, 13 patients have been implanted with the UCSF/Storz device, 10 of whom have been fitted with their external processor and transmitter and have received at least their initial postoperative evaluations. Of these 10 patients, nine are able to use all four channels of their implant system. The device fitting/adjusting process for these patients has been remarkably easy, requiring only approximately 30 to 60 minutes. Patient results have been extremely good, with eight of the 10 patients obtaining some open-set auditory only speech understanding. Without extensive rehabilitation and training, most patients have demonstrated an improvement in speech reception over time. Lip-reading and tracking results indicate that all patients have attained an enhancement of lip-reading ability with the use of the device, suggesting that improved general communication skills have been provided for each UCSF/Storz patient.

The Minimal Auditory Capabilities (MAC) Battery was administered individually to 75 hearing aid users with profound sensorineural hearing loss. The purposes of the study were (1) to determine the reliability of the individual tests, their range of difficulty, and their intercorrelations; (2) to undertake a standardization procedure based on data from this population; and (3) to assess the need for revisions. Difficulty ranged gradually from a mean score of 86% correct for the Spondee Same/Different test to a mean of 16% for the NU 6 monosyllabic word test. Alpha estimates of reliability were 0.89 or higher for all but the Everyday Sounds test (0.85), the Question/Statement test (0.83), and the Spondee Same/Different test (0.81). Along with the reliability and range of difficulty results, interest correlations provided no indication that any of the tests should be discarded. In the standardization of the MAC, the mean score correct on each test was set at 100 and the standard deviation at 10. Prepared tables for immediate conversion of a raw score to a standardized score for any test are included in an Appendix. Among revisions, also listed in the Appendix, the CID Everyday Sentences test was reduced to 20 items from 40, the SPIN High-Context Sentences were assigned key words, and the assessment of distinctive feature identification was discontinued.

Sixteen patients have been implanted with the UCSF/Storz multichannel implant, 11 of whom have been fitted with their external speech processors and transmitters and administered postoperative audiological evaluations. Both the surgical procedures used and the hearing results for these patients are presented. The potential medical/surgical complications of implant surgery and the future direction of research and development within the UCSF/Storz implant program are discussed.

Using the four channel cochlear implant system with a vocoder-based processor developed at UCSF over an extensive period of research, clinical trials of the UCSF/Storz device were initiated in February 1985, under the sponsorship of Storz Instrument Company. To date, 13 patients have been implanted with this device, nine of whom have been fitted with their external processor and transmitter and have received at least their initial postoperative evaluation. Patient results have been extremely promising, with eight of the nine patients obtaining some open-set auditory only speech understanding. Most patients have demonstrated improvement over time and all patients have attained an enhancement in lipreading ability with the use of the UCSF/Storz device.