The Swiss heroin trials: testing alternative approaches

Over half a million heroin misusers receive oral methadone maintenance treatment world-wide1 but the maintenance prescription of injectable opioid drugs, like heroin, remains controversial. In 1992 Switzerland began a large scale evaluation of heroin and other injectable opiate prescribing that eventually involved 1035 misusers. 2 3 The results of the evaluation have recently been reported.4 These show that it was feasible to provide heroin by intravenous injection at a clinic, up to three times a day, for seven days a week. This was done while maintaining good drug control, good order, client safety, and staff morale. Patients were stabilised on 500 to 600 mg heroin daily without evidence of increasing tolerance. Retention in treatment was 89% at six months and 69% at 18 months.4 The self reported use of non-prescribed heroin fell signifianctly, but other drug use was minimally affected. The death rate was 1% per year, and there were no deaths from overdose among participants . . . [Full text of this article]

Acute intermittent porphyria: alternative splicing of hydroxymethylbilane synthase mRNA excludes exons 3 and 12

The hydroxymethylbilane synthase (HMBS) mRNAs from 44 control individuals and 30 patients suffering from acute intermittent porphyria (AIP), were screened for length differences by reverse transcriptase polymerase chain reaction (RT-PCR) and any abnormalities were characterized by direct sequencing. Examination of the mRNAs extracted from the peripheral blood lymphocytes of the samples revealed varying degrees of alternative splicing, involving the removal of exons 3 and 12. Approximately 10-50% of the mRNA molecules were affected, despite the absence of genomic splice site mutations or any major deviance from consensus splice sequence values. The preliminary data obtained from this study suggest that this event is a normal occurrence in peripheral blood lymphocytes, and may not be associated with the molecular pathology responsible for AIP. (C) 1998 Academic Press Limited.

An evaluation of selective Helicoverpa armigera control options in sweet corn

Helicoverpa armigera is a serious insect pest of sweet corn in Australia and is becoming increasingly difficult to manage with conventional chemical insecticides due to resistance problems. A number of alternative H. armigera control options were evaluated in sweet corn and compared with deltamethrin and no action (control). The alternative tactics evaluated were: heliothis nuclear polyhedrosis virus plus Trichogramma nr. brassicae releases; Bacillus thuringiensis; and Trichogramma alone. The H. tea nuclear polyhedrosis virus + Trichogramma plots had the lowest cob damage (6.0%), followed by the B. thuringiensis plots (12.0%), Trichogramma alone plots (20.2%), control plots (23.2%) and deltamethrin plots (53.5%). There was no evidence to suggest that the Trichogramma nr. brassicae releases had any impact on H. armigera egg mortality. However, there was a large natural population of Trichogramma pretiosum in all plots. The application of deltamethrin reduced the action of these wasps and predators, resulting in higher larval infestation and significantly more cob damage. The findings indicate that the pathogens heliothis nuclear polyhedrosis virus and B. thuringiensis can effectively control H. armigera when their action complements high natural levels of egg parasitism, and that they have potential for use in integrated pest management programs in sweet corn.

Post-transcriptional regulation of the GLI1 oncogene by the expression of alternative 5 ' untranslated regions

The oncogene GLI1 is involved in the formation of basal cell carcinoma and other tumor types as a result of the aberrant signaling of the Sonic hedgehog-Patched pathway. In this study, we have identified alternative GLI1 transcripts that differ in their 5' untranslated regions (UTRs) and are generated by exon skipping. These are denoted (alpha -UTR, beta -UTR, and gamma -UTR according to the number of noncoding exons possessed (three, two, and one, respectively). The alpha- and beta -UTR forms represent the major Gli1 transcripts expressed in mouse tissues, whereas the gamma -UTR is present at relatively low levels but is markedly induced in mouse skin treated with 12-O-tetradecanoylphorbol 13-acetate, Transcripts corresponding to the murine beta and gamma forms were identified in human tissues, but significantly, only the gamma -UTR form was present in basal cell carcinomas and in proliferating cultures of a keratinocyte cell line. Flow cytometry analysis determined that the gamma -UTR variant expresses a heterologous reporter gene 14-23-fold higher than the alpha -UTR and 5-13-fold higher than the beta -UTR in a variety of cell types. Because expression of the gamma -UTR variant correlates with proliferation, consistent with a role for GLI1 in growth promotion, up-regulation of GLI1 expression through skipping of 5' noncoding exons may be an important tumorigenic mechanism.

Mango stem-end rot (Botryosphaeria dothidea) disease control by partial-pressure infiltration of fungicides

The in vitro efficacy of several fungicides against Botryosphaeria dothidea (syn. Dothiorella dominicana) and their in vivo efficacy in controlling mango cv. Kensington Pride stem-end rot on partial-pressure infiltration v. dip treatment of green mature fruit was evaluated. In vitro sensitivity of B. dothidea to Benlate (benomyl), Sportak (prochloraz) and Scala (pyrimethanil) at 10 dilutions of the manufacturer's recommended rate was first determined at typical cold (13degreesC) and shelf (23degreesC) storage temperatures. The effectiveness of partial-pressure infiltration and conventional hot (52degreesC) or cold (26degreesC) dipping of fruit after harvest was then evaluated using the commercially recommended rate for each fungicide. In vitro, Benlate and Sportak prevented the growth of B. dothidea at both storage temperatures and at all concentrations, while Scala partially controlled growth of the pathogen. Benlate was the most effective fungicide for stem-end rot control. Sportak and Scala resulted in stem-end rot control when applied by partial-pressure infiltration, but not as dips. Partial-pressure infiltration holds promise for enhancing the efficacy of otherwise less effective but alternative fungicides for control of stem-end rot diseases.

A framework for extreme-event control in wastewater treatment

In this paper an approach to extreme event control in wastewater treatment plant operation by use of automatic supervisory control is discussed. The framework presented is based on the fact that different operational conditions manifest themselves as clusters in a multivariate measurement space. These clusters are identified and linked to specific and corresponding events by use of principal component analysis and fuzzy c-means clustering. A reduced system model is assigned to each type of extreme event and used to calculate appropriate local controller set points. In earlier work we have shown that this approach is applicable to wastewater treatment control using look-up tables to determine current set points. In this work we focus on the automatic determination of appropriate set points by use of steady state and dynamic predictions. The performance of a relatively simple steady-state supervisory controller is compared with that of a model predictive supervisory controller. Also, a look-up table approach is included in the comparison, as it provides a simple and robust alternative to the steady-state and model predictive controllers, The methodology is illustrated in a simulation study.

Thermodynamic non-ideality as an alternative source of the effect of sucrose on the thrombin-catalyzed hydrolysis of peptide p-nitroanalide substrates

The inhibitory effect of sucrose on the kinetics of thrombin-catalyzed hydrolysis of the chromogenic substrate S-2238 (D-phenylalanyl-pipecolyl-arginoyl-p-nitroanilide) is re-examined as a possible consequence of thermodynamic non-ideality-an inhibition originally attributed to the increased viscosity of reaction mixtures. However, those published results may also be rationalized in terms of the suppression of a substrate-induced isomerization of thrombin to a slightly more expanded (or more asymmetric) transition state prior to the irreversible kinetic steps that lead to substrate hydrolysis. This reinterpretation of the kinetic results solely in terms of molecular crowding does not signify the lack of an effect of viscosity on any reaction step(s) subject to diffusion control. Instead, it highlights the need for development of analytical procedures that can accommodate the concomitant operation of thermodynamic non-ideality and viscosity effects.

Use of complementary and alternative medicine and quality of life: changes at the end of life

The purpose of this study was to compare the physical, psychological and social dimensions associated with quality-of-life outcomes over the last year of life, between advanced cancer users and nonusers of complementary and alternative medicine. One hundred and eleven patients were identified through Queensland Cancer Registry records, and followed up every four to six weeks until close to death using standardized protocols. Outcome measures were symptom burden, psychological distress, subjective wellbeing, satisfaction with conventional medicine and need for control over treatment decisions. At the initial interview, 36 (32%) participants had used complementary/ alternative medicine the previous week; mainly vitamins, minerals and tonics and herbal remedies. Among all participants, 53 (48%) used at least one form of complementary/ alternative medicine over the study period. Only six (11%) visited alternative practitioners on a regular basis. Overall, complementary/ alternative medicine users reported higher levels of anxiety and pain, less satisfaction with conventional medicine and lower need for control over treatment decisions compared with nonusers. These differences tend to change as death approaches. A more rigorous assessment of complementary/ alternative medicine use, psychological distress, pain and subjective wellbeing among patients with advanced cancer is needed in the clinical setting.

Multiple tissue-specific promoters control expression of the murine tartrate-resistant acid phosphatase gene

Tartrate-resistant acid phosphatase (TRAP) is highly expressed in osteoclasts and in a subset of tissue macrophages and dendritic cells. It is expressed at lower levels in the parenchymal cells of the liver, glomerular mesangial cells of the kidney and pancreatic acinar cells. We have identified novel TRAP mRNAs that differ in their 5-untranslated region (5'-UTR) sequence, but align with the known murine TRAP mRNA from the first base of Exon 2. The novel 5'-UTRs represent alternative first exons located upstream of the known 5'-UTR. A similar genomic structure exists for the human TRAP gene with partial conservation of the exon and promoter sequences. Expression of the most distal 5'-UTR (Exon 1A) is restricted to adult bone and spleen tissue. Exon 1B is expressed primarily in tissues containing TRAP-positive nonhaematopoietic cells. The known TRAP 5'-UTR (Exon 1) is expressed in tissues characteristic of myeloid cell expression. In addition the Exon 1C promoter sequence is shown to comprise distinct transcription start regions, with an osteoclast-specific transcription initiation site identified downstream of a TATA-like element. Macrophages are shown to initiate transcription of the Exon 1C transcript from a purine-rich region located upstream of the osteoclast-specific transcription start point. The distinct expression patterns for each of the TRAP 5'-UTRs suggest that TRAP mRNA expression is regulated by the use of four alternative tissue- and cell-restricted promoters. (C) 2003 Elsevier Science B.V. All rights reserved.

A prospective study of the use of alternative therapies by men with localized prostate cancer

Although the use of alternative therapies is highly prevalent amongst men with prostate cancer, research about the predictors of such use is limited. The current study aimed to describe prospectively the use of alternative therapies by men diagnosed with localized prostate cancer and identify predictors of alternative therapy use. In all, 111 men newly diagnosed with localized prostate cancer (93% response) were recruited to the study prior to treatment. Men's use of alternative therapies and psychological variables including: psychological distress, orientation to health care, decisional conflict, and health locus of control, were assessed at three time points-(1) before treatment; (2) 2 months after completion of treatment; and (3) 12 months after completion of treatment. Demographic information was also obtained. The percentage of men using alternative therapies was 25, 17 and 14% before treatment, 2 and 12 months after treatment, respectively. In general, the most commonly used therapies were dietary changes, vitamins and herbal and nutrient remedies. Alternative therapy use was not related to final treatment choices. Before treatment, men who used alternative therapies were more uncertain about prostate cancer compared to men who were not using these therapies. Men who were using alternative therapies 12 months after treatment were less psychologically distressed that men who were not using these therapies. Health locus of control and orientation to health care were not found to be related to men's use of alternative therapies. In conclusion, men's use of alternative therapies after localized prostate cancer varied across time in terms of the incidence of use, the types of therapies used, and the psychological correlates of therapy use. Informational support that targets uncertainty about prostate cancer may assist men at diagnosis who are considering alternative therapy use. The potential for alternative therapies to have a supportive function in patient care requires further investigation. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

GCMC-surface area of carbonaceous materials with N-2 and Ar adsorption as an alternative to the classical BET method

In this paper we apply a new method for the determination of surface area of carbonaceous materials, using the local surface excess isotherms obtained from the Grand Canonical Monte Carlo simulation and a concept of area distribution in terms of energy well-depth of solid–fluid interaction. The range of this well-depth considered in our GCMC simulation is from 10 to 100 K, which is wide enough to cover all carbon surfaces that we dealt with (for comparison, the well-depth for perfect graphite surface is about 58 K). Having the set of local surface excess isotherms and the differential area distribution, the overall adsorption isotherm can be obtained in an integral form. Thus, given the experimental data of nitrogen or argon adsorption on a carbon material, the differential area distribution can be obtained from the inversion process, using the regularization method. The total surface area is then obtained as the area of this distribution. We test this approach with a number of data in the literature, and compare our GCMC-surface area with that obtained from the classical BET method. In general, we find that the difference between these two surface areas is about 10%, indicating the need to reliably determine the surface area with a very consistent method. We, therefore, suggest the approach of this paper as an alternative to the BET method because of the long-recognized unrealistic assumptions used in the BET theory. Beside the surface area obtained by this method, it also provides information about the differential area distribution versus the well-depth. This information could be used as a microscopic finger-print of the carbon surface. It is expected that samples prepared from different precursors and different activation conditions will have distinct finger-prints. We illustrate this with Cabot BP120, 280 and 460 samples, and the differential area distributions obtained from the adsorption of argon at 77 K and nitrogen also at 77 K have exactly the same patterns, suggesting the characteristics of this carbon.

Understanding alternative splicing: Towards a cellular code

In violation of the 'one gene, one polypeptide' rule, alternative splicing allows individual genes to produce multiple protein isoforms - thereby playing a central part in generating complex proteomes. Alternative splicing also has a largely hidden function in quantitative gene control, by targeting RNAs for nonsense-mediated decay. Traditional gene-by-gene investigations of alternative splicing mechanisms are now being complemented by global approaches. These promise to reveal details of the nature and operation of cellular codes that are constituted by combinations of regulatory elements in pre-mRNA substrates and by cellular complements of splicing regulators, which together determine regulated splicing pathways.