Development and characterization of novel potent and stable inhibitors of endopeptidase EC 3.4.24.15

Solid-phase synthesis was used to prepare a series of modifications to the selective and potent inhibitor of endopeptidase EC 3.4.24.15 (EP24.15), N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), which is degraded at the Ala-Tyr bond, thus severely limiting its utility in vivo. Reducing the amide bond between the Ala and Tyr decreased the potency of the inhibitor to 1/1000. However, the replacement of the second alanine residue immediately adjacent to the tyrosine with alpha-aminoisobutyric acid gave a compound (JA-2) that was equipotent with cFP, with a K-i of 23 nM. Like cFP, JA-2 inhibited the closely related endopeptidase EC 3.4.24.16 1/20 to 1/30 as potently as it did EP24.15, and did not inhibit the other thermolysin-like endopeptidases angiotensin-converting enzyme, endothelin-converting enzyme and neutral endopeptidase. The biological stability of JA-2 was investigated by incubation with a number of membrane and soluble sheep tissue extracts. In contrast with cFP, JA-2 remained intact after 48 h of incubation with all tissues examined. Further modifications to the JA-2 compound failed to improve the potency of this inhibitor. Hence JA-2 is a potent, EP24.15-preferential and biologically stable inhibitor, therefore providing a valuable tool for further assessing the biological functions of EP24.15.

Contemporary strategies for rural community development in Australia: a governmentality perspective

Contemporary strategies for rural development in Australia are based upon notions of self-help and bottom-up, community-based initiatives which are said to 'empower' the individual from the imposing structures of government intervention. While such strategies are not entirely new to Australia, they have, it seems, been inadequately theorised to date and are generally regarded, in rather functionalist terms, as indicative of attempts to cut back on public expenditure. Harnessing itself to the 'governmentality' perspective, this paper explores government and 'expert' discourses of rural community development in Queensland and suggests, instead, that these strategies are indicative of an advanced liberal form of rule which seeks to 'govern through community'. With this in mind, three basic research questions are identified as worthy of further exploration; how are the notions of self-governing individuals and communities constructed in political discourse; what political rationalities are used to justify current levels of(non) intervention and finally; what are the discourses, forms and outcomes of empowerment at the local level? The paper concludes by arguing that while the empowering effects of self-help are frequently cited as its greatest virtue, it is not so much control as the added burden of responsibility that is being devolved to local people. Given the emphasis of the governmentality perspective on strategies for 'governing at a distance', however, these conclusions can hardly be unexpected. (C) 2000 Elsevier Science Ltd, All rights reserved.

Effect of increased lung expansion on lung growth and development near midgestation in fetal sheep

Obstruction of the fetal trachea is a potent stimulus for fetal lung growth and may have therapeutic potential in human fetuses with lung hypoplasia. However, the effects of increased lung expansion on lung development near midgestation, which is the preferred timing for fetal intervention, have not been well studied. Our aim was to determine the effects of increased lung expansion on lung development at 75-90 d of gestation in fetal sheep. In three groups of fetuses (n = 4 for each), the trachea was occluded for either 10 [10-d tracheal occlusion (TO) group] or 15 d (15-d TO group) or left intact (control fetuses). TO for both 10 and 15 d caused fetal hydrops, resulting in significantly increased fetal body weights. Both periods of TO significantly increased total lung DNA contents from 99.8 +/- 10.1 to 246.0 +/- 5.3 and 246.9 +/- 48.7 mg in 10- and 15-d TO fetuses, respectively. TO for 10 and 15 d also increased airspace diameter, although the percentage of lung occupied by airspace was not increased in 10-d TO fetuses due to large increases in interairway distances; this resulted from a large increase in mesenchymal tissue. The interairway distances at 15 d of TO were reduced compared with the 10-d value but were still similar to 30% larger than control values. We conclude that TO at

Development and standardization of the Self-regulation Skills Interview (SRSI): A new clinical assessment tool for acquired brain injury

The Self-regulation Skills Interview (SRSI) is a clinical tool designed to measure a range of metacognitive skills essential for rehabilitation planning, monitoring an individual's progress, and evaluating the outcome of treatment interventions. The results of the present study indicated that the SRSI has sound interrater reliability and test-retest reliability. A principle components analysis revealed three SRSI factors: Awareness, Readiness to Change, and Strategy Behavior. A comparison between a group of 61 participants with acquired brain injury (ABI) and a group of 43 non-brain-injured participants indicated that the participants with ABI had significantly lower levels of Awareness and Strategy Behavior, but that level of Readiness to Change was not significantly different between the two groups. The significant relationship observed between the SRSI factors and measures of neuropsychological functioning confirmed the concurrent validity of the scale and supports the value of the SRSI for post-acute assessment.

Computational chemistry on Fujitsu vector-parallel processors: Development and performance of applications software

In this and a preceding paper, we provide an introduction to the Fujitsu VPP range of vector-parallel supercomputers and to some of the computational chemistry software available for the VPP. Here, we consider the implementation and performance of seven popular chemistry application packages. The codes discussed range from classical molecular dynamics to semiempirical and ab initio quantum chemistry. All have evolved from sequential codes, and have typically been parallelised using a replicated data approach. As such they are well suited to the large-memory/fast-processor architecture of the VPP. For one code, CASTEP, a distributed-memory data-driven parallelisation scheme is presented. (C) 2000 Published by Elsevier Science B.V. All rights reserved.

Survival and development of Helicoverpa armigera (Hubner) (Lepidoptera : Noctuidae) on neem (Azadirachta indica A. Juss) leaves

The survival, development and feeding responses of Helicoverpa armigera (Hubner) on neem (Azadirachta indica A. Juss) leaflets were evaluated under choice and no-choice conditions. Neem leaflets provided to starving fourth-instar larvae were chewed, but larvae expectorated most of the material. The weight of surviving larvae decreased and no fourth instars completed development on neem leaflets alone. Larvae resumed feeding when transferred to cotton leaves after 5 days of feeding on neem leaflets. Fourth instars strongly discriminated between neem leaflets and cotton leaves when offered a choice. Early sixth instars decreased in weight and had delayed development when feet only on neem leaflets. Mure than one-half lived for more than 2 weeks and some completed development to adults. Neem is an unacceptable non-host plant species for H. armigera.

Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat

Our previous studies indicate that oxycodone is a putative kappa-opioid agonist, whereas morphine is a well documented mu-opioid agonist. Because there is limited information regarding the development of tolerance to oxycodone, this study was designed to 1) document the development of tolerance to the antinociceptive effects of chronically infused i.v. oxycodone relative to that for i.v. morphine and 2) quantify the degree of antinociceptive cross-tolerance between morphine and oxycodone in adult male Dark Agouti (DA) rats. Antinociceptive testing was performed using the tail-flick latency test. Complete antinociceptive tolerance was achieved in 48 to 84 h after chronic infusion of equi-antinociceptive doses of i.v. oxycodone (2.5 mg/24 h and 5 mg/24 h) and i.v. morphine (10 mg/24 h and 20 mg/24 h, respectively). Dose-response curves for bolus doses of i.v. and i.c.v. morphine and oxycodone were produced in naive, morphine-tolerant, and oxycodone-tolerant rats. Consistent with our previous findings that oxycodone and morphine produce their intrinsic antinociceptive effects through distinctly different opioid receptor populations, there was no discernible cross-tolerance when i.c.v. oxycodone was given to morphine-tolerant rats. Similarly, only a low degree of cross-tolerance (approximate to 24%) was observed after i.v. oxycodone administration to morphine-tolerant rats. By contrast, both i.v. and i.c.v. morphine showed a high degree of cross-tolerance (approximate to 71% and approximate to 54%, respectively) in rats rendered tolerant to oxycodone. Taken together, these findings suggest that, after parenteral but not supraspinal administration, oxycodone is metabolized to a mu-opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.

The development and evaluation of an incontinence screening questionnaire for female primary care

Although there is a high prevalence of leaking urine among Australian women, there are currently no standardized procedures for screening patients for incontinence in the primary care setting (known in Australia as general practice). In response to this, an incontinence screening questionnaire (ISQ) was developed and evaluated for use in general practice. Eighty-nine women completed an original compilation of 33 items that asked about situations associated with leaking urine, avoidance of leakage, and concern about leakage. Each item was assessed according to its acceptability for the population of female general practice patients, discriminative value, and test-retest reliability. These patients also underwent an objective test of incontinence, the 48-hour pad test, so that the screening items could be validated against an objective classification of incontinence. The study included women who had bladder control problems and those who did not. Eight items on the ISQ were shown to be acceptable to patients, discriminative, reliable, and valid indicators of objective incontinence. Five items were capable of predicting almost 70% of patients who showed objective leakage of urine and misclassified fewer than 15% of these patients. Those five items were selected for inclusion in the (refined) ISQ. (C) 2000 Wiley-Liss, Inc.

Assessing perceived need for mental health care in a community survey: development of the Perceived Need for Care Questionnaire (PNCQ)

Background: The Perceived Need for Care Questionnaire (PNCQ) was designed for the Australian National Survey of Mental Health and Wellbeing. The PNCQ complemented collection of data on diagnosis and disability with the survey participants' perceptions of their needs for mental health care and the meeting of those needs. The four-stage design of the PNCQ mimics a conversational exploration of the topic of perceived needs. Five categories of perceived need are each assigned to one of four levels of perceived need (no need, unmet need, partially met need and met need). For unmet need and partially met need, information on barriers to care is collected, Methods: Inter-rater reliabilities of perceived needs assessed by the PNCQ were examined in a study of 145 anxiety clinic attenders. Construct validity of these items was tested, using a multi-trait multi-method approach and hypotheses regarding extreme groups, in a study with a sample of 51 general practice and community psychiatric service patients. Results: The instrument is brief to administer and has proved feasible for use in various settings. Inter-rater reliabilities for major categories, measured by the kappa statistic, exceeded 0.60 in most cases; for the summary category of all perceived needs, inter-rater reliability was 0.62. The multi-trait multi-method approach lent support to the construct validity of the instrument, as did findings in extreme groups. Conclusions: The PNCQ shows acceptable feasibility, reliability and validity, adding to the range of assessment tools available for epidemiological and health services research.

Effects of replacing meat with soyabean in the diet on sex hormone concentrations in healthy adult males

A randomised crossover dietary intervention study was performed to evaluate the effects of replacing meat protein in the diet with a soyabean product, tofu, on blood concentrations of testosterone, dihydrotestosterone, androstanediol glucuronide, oestradiol, sex hormone-binding globulin (SHBG), and the free androgen index (total testosterone concentration/SHBG concentration x 100; FAI). Forty-two healthy adult males aged 35-62 years were studied. Diets were isoenergetic, with either 150 g lean meat or 290 g tofu daily providing an equivalent amount of macronutrients, with only the source of protein differing between the two diets. Each diet lasted for 4 weeks, with a 2-week interval between interventions. Fasting blood samples were taken between 07.00 and 09.30 hours. Urinary excretion of genistein and daidzein was significantly higher after the tofu diet (P

Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA

Two small RNAs regulate the timing of Caenorhabditis elegans development(1,2). Transition from the first to the second larval stage fates requires the 22-nucleotide lin-4 RNA(1,3,4), and transition from late larval to adult cell fates requires the 21-nucleotide let-7 RNA 2. The lin-4 and let-7 RNA genes are not homologous to each other, but are each complementary to sequences in the 3' untranslated regions of a set of protein-coding target genes that are normally negatively regulated by the RNAs1,2,5,6. Here we have detected let-7 RNAs of similar to 21 nucleotides in samples from a wide range of animal species, including vertebrate, ascidian, hemichordate, mollusc, annelid and arthropod, but not in RNAs from several cnidarian and poriferan species, Saccharomyces cerevisiae, Escherichia coli or Arabidopsis. We did not detect lin-4 RNA in these species. We found that let-7 temporal regulation is also conserved: let-7 RNA expression is first detected at late larval stages in C. elegans and Drosophila, at 48 hours after fertilization in zebrafish, and in adult stages of annelids and molluscs. The let-7 regulatory RNA may control late temporal transitions during development across animal phylogeny.

Detecting insomnia: comparison of four self-report measures of sleep in a young adult population

The sensitivity and specificity of four self-report measures of disordered sleep - the Sleep Impairment Index (SII), the Sleep Disorders Questionnaire (SDQ), the Dysfunctional Beliefs and Attitudes About Sleep Scale (DBAS) and the Sleep-Wake Activity Inventory (SWAI) - were compared in subjects with insomnia and normal sleep. Nineteen young adult subjects met DSM-IV criteria for primary insomnia and another 19 were normal control subjects. Discriminatory characteristics of each measure were assessed using receiver operator characteristic curve analyses. Discriminatory power was maximised for each measure to produce cut-scores applicable for identification of individuals with insomnia. The DBAS, SII and SDQ psychiatric DIMS subscale were found to correlate, and discriminated well between the two groups. The SWAI nocturnal sleep subscale was not found to be an accurate discriminator. The results suggest differences in the measures in their ability to detect insomnia, and offer guidelines as to the optimal use of test scores to identify young adults suspected of insomnia.