Dynamic character of charge transport parameters in disordered organic semiconductor field-effect transistors.

In this perspective article, we discuss the dynamic instability of charge carrier transport in a range of popular organic semiconductors. We observe that in many cases field-effect mobility, an important parameter used to characterize the performance of organic field-effect transistors (OFETs), strongly depends on the rate of the gate voltage sweep during the measurement. Some molecular systems are so dynamic that their nominal mobility can vary by more than one order of magnitude, depending on how fast the measurements are performed, making an assignment of a single mobility value to devices meaningless. It appears that dispersive transport in OFETs based on disordered semiconductors, those with a high density of localized trap states distributed over a wide energy range, is responsible for the gate voltage sweep rate dependence of nominal mobility. We compare such rate dependence in different materials and across different device architectures, including pristine and trap-dominated single-crystal OFETs, as well as solution-processed polycrystalline thin-film OFETs. The paramount significance given to a single mobility value in the organic electronics community and the practical importance of OFETs for applications thus suggest that such an issue, previously either overlooked or ignored, is in fact a very important point to consider when engaging in fundamental studies of charge carrier mobility in organic semiconductors or designing applied circuits with organic semiconductors.

"On" state freezing of gait in Parkinson disease: a paradoxical levodopa-induced complication.

OBJECTIVE: To describe the phenotype of levodopa-induced "on" freezing of gait (FOG) in Parkinson disease (PD). METHODS: We present a diagnostic approach to separate "on" FOG (deterioration during the "on state") from other FOG forms. Four patients with PD with suspected "on" FOG were examined in the "off state" (>12 hours after last medication intake), "on state" (peak effect of usual medication), and "supra-on" state (after intake of at least twice the usual dose). RESULTS: Patients showed clear "on" FOG, which worsened in a dose-dependent fashion from the "on" to the "supra-on" state. Two patients also demonstrated FOG during the "off state," of lesser magnitude than during "on." In addition, levodopa produced motor blocks in hand and feet movements, while other parkinsonian features improved. None of the patients had cognitive impairment or a predating "off" FOG. CONCLUSIONS: True "on" FOG exists as a rare phenotype in PD, unassociated with cognitive impairment or a predating "off" FOG. Distinguishing the different FOG subtypes requires a comprehensive motor assessment in at least 3 medication states.

Charles Theodore Dotter. The father of intervention.

The 1st percutaneous transluminal angioplasty marked a new era in the treatment of peripheral atherosclerotic lesions. The early techniques used in peripheral percutaneous transluminal angioplasty form the basis for subsequent percutaneous intervention both in the peripheral and coronary arteries and are largely the contribution of Charles Dotter. Dotter was the 1st to describe flow-directed balloon catheterization, the double-lumen balloon catheter, the safety guidewire, percutaneous arterial stenting, and more. This practical genius dedicated his considerable energy to the belief that there is always a better way to treat disease. His personal contributions to clinical medicine, research, and teaching have saved millions of limbs and lives all over the world.

Treadmill exercise during adenosine infusion is safe, results in fewer adverse reactions, and improves myocardial perfusion image quality.

BACKGROUND: Combining low-level treadmill exercise with adenosine infusion may result in fewer bradyarrhythmic complications by increasing sympathetic tone and may improve myocardial perfusion image quality by decreasing background activity. METHODS: Patients referred for outpatient pharmacologic stress myocardial perfusion imaging performed simultaneous treadmill exercise (mean 2.2 metabolic equivalents) throughout 6-minute adenosine infusion (adenosine-exercise n = 507). Patients unable to exercise and those with left bundle branch block received adenosine infusion alone (adenosine-nonexercise n = 286). Adverse reaction data were collected on all patients and compared by sex. Background-to-target activity was calculated in a blinded fashion on 200 randomly selected patients. RESULTS: During the period from April 1996 to December 1998, 507 patients (64%) underwent adenosine-exercise testing, whereas 286 (36%) underwent adenosine-nonexercise testing. Hypotensive and arrhythmic (atrioventricular block, sinus bradycardia, and new onset atrial fibrillation or flutter) adverse reactions occurred less often during adenosine-exercise than during adenosine-nonexercise. Neither death nor myocardial infarction occurred in either group. In the adenosine-exercise group, 2.8% of patients experienced an adverse reaction versus 5.6% of the adenosine-nonexercise group (P = .04). The reduction in adverse reactions occurred in both men and women, although women had significantly more adverse reactions than men (5.7% vs 1.8%, P = .004). Liver/heart and gut/heart ratios were lower in the adenosine-exercise group (1.05+/-0.42 vs. 1.21+/-0.55 , P = .01; 0.61+/-0.21 vs. 0.69+/-0.24, P = .03, respectively). CONCLUSIONS: Compared with adenosine infusion alone, combining low-level treadmill exercise with adenosine in outpatients is safe, better tolerated, and improves image quality. Women were more likely to experience adverse reactions than men.

Surveillance of occupational diseases in the United States. A survey of activities and determinants of success.

Managers of state-based occupational disease surveillance programs were interviewed for information on their program's characteristics and factors that contributed to their success. There were 68 programs in 52 jurisdictions (50 states, the District of Columbia and New York City). Reportable conditions ranged from a specific disease to "all occupational diseases". Of these programs, 56% met at least one of their objectives. Conditions associated with successful programs usually had short latency periods, were easily diagnosed, and were related to a workplace hazard. They included agricultural injuries, burns, respiratory diseases, cumulative trauma disorders, and poisonings due to lead, pesticides, or carbon monoxide. Successful programs had larger budgets and more staff than did unsuccessful programs, and also took actions after notification of a condition.

Role of glutathione S-transferases in the resistance of human colon cancer cell lines to doxorubicin.

The anthracycline doxorubicin has little activity against colorectal cancers. It is hypothesized that this is attributable to a multifactorial resistance mechanism in which the glutathione S-transferases (GST) may play a role. We studied the relationship between GST expression and doxorubicin resistance in four human colon adenocarcinoma cell lines (HT-29, LoVo, SW620, and Caco-2), with the goal of modulating GST activity to overcome resistance. Caco-2 cells were the most resistant to doxorubicin, showing an IC50 value approximately 80- to 90-fold higher than HT-29 or LoVo and 600-fold higher than SW620. Total GST catalytic activity was significantly higher in Caco-2 cells compared with the other lines. All four cell lines expressed GST-pi at the catalytic activity, protein, and mRNA levels; however, no significant differences were observed among the cell lines. GST-mu expression was not detectable at the protein and mRNA levels, and the four cell lines displayed very low catalytic activity toward a GST-mu-selective substrate. Caco-2 cells showed a unique, highly expressed GST-alpha-immunoreactive band that was not detected in the other lines; however, the glutathione peroxidase activity of Caco-2 cells was the lowest among the four cell lines. Neither ethacrynic acid nor glutathione analogues that function as GST class-selective inhibitors were able to potentiate the cytotoxic effects of doxorubicin in these colon cancer cell lines, as demonstrated in both microplate colorimetric and clonogenic assays. The multidrug resistance-associated protein and P-glycoprotein were either not detectable or expressed at such low levels that they are not likely to contribute to the differences in doxorubicin sensitivity observed among these cell lines.

Correspondence between nasalance scores and listener judgments of hypernasality and hyponasality.

The relationship between nasalance scores and perceptual judgments of hypernasality and hyponasality was examined for 74 subjects (51 with cleft palate and 23 noncleft controls). Twenty-nine of the 51 subjects with cleft palate had received pharyngeal flap surgery. Predictive analyses were performed to assess the sensitivity, specificity, and efficiency of the Nasometer as a screening instrument. The overall relationship between perceptual judgments of hypernasality and nasalance scores was good for the nonflap subjects when a nasalance cutoff score of 26 was used. A sensitivity coefficient of 0.87 and a specificity coefficient of 0.93 were obtained. Ninety-one percent of the nasometry-based classifications accurately reflected listener judgments of hypernasality. The correspondence between nasalance scores and clinical judgments of hyponasality was also good for the nonflap subjects when a nasalance cutoff score of 50 was used. Ninety-one percent of these classifications were consistent with the listener judgments. Efficiency of nasometry was poorer for the flap subjects.

Production of mouse epidermal growth factor in yeast: high-level secretion using Pichia pastoris strains containing multiple gene copies.

We have constructed a synthetic secretion cassette encoding the alpha-factor prepro leader peptide from Saccharomyces cerevisiae fused to mouse epidermal growth factor (mEGF). This was used to compare the secretion of mEGF, a 53-amino acid polypeptide, in S. cerevisiae and Pichia pastoris. In both yeasts the leader sequence was accurately and efficiently cleaved showing that the S. cerevisiae-derived alpha-factor prepro region is correctly recognised and processed in P. pastoris. Of the total mEGF produced, over 90% was exported to the culture supernatant, although the final level of accumulation was dependent on the composition of the growth medium. With P. pastoris there was instability of the protein in minimal medium (yeast nitrogen base), probably caused by extracellular proteases. This was overcome by adding 1% Casamino acids and buffering the medium to pH 6.0. To increase the level of secreted mEGF we have developed a method for rapidly screening large numbers of P. pastoris transformants for the presence of many copies of a foreign gene. Using this procedure we isolated a strain containing 19 integrated copies of the mEGF gene which secreted 450 micrograms/ml of mEGF in high-density fermentations. Characterisation of the yeast-derived mEGF showed the presence of truncated forms, mEGF1-51 and mEGF1-52, as was found with S. cerevisiae-secreted human EGF [George-Nascimento et al., Biochemistry 27 (1988) 797-802]. In addition, the full-length protein, mEGF1-53, was secreted by P. pastoris.

Expression of tetanus toxin fragment C in yeast: gene synthesis is required to eliminate fortuitous polyadenylation sites in AT-rich DNA.

Fragment C is a non-toxic 50 kDa fragment of tetanus toxin which is a candidate subunit vaccine against tetanus. The AT-rich Clostridium tetani DNA encoding fragment C could not be expressed in Saccharomyces cerevisiae due to the presence of several fortuitous polyadenylation sites which gave rise to truncated mRNAs. The polyadenylation sites were eliminated by chemically synthesising the DNA with increased GC-content (from 29% to 47%). Synthesis of the entire gene (1400 base pairs) was necessary to generate full-length transcripts and for protein production in yeast. Using a GAL1 promoter vector, fragment C was expressed to 2-3% of soluble cell protein. Fragment C could also be secreted using the alpha-factor leader peptide as a secretion signal. The protein was present at 5-10 mg/l in the culture medium in two forms: a high molecular mass hyper-glycosylated protein (75-200 kDa) and a core-glycosylated protein (65 kDa). Intracellular fragment C was as effective in vaccinating mice against tetanus authentic fragment C. The glycosylated material was inactive, though it was rendered fully active by de-glycosylation.