Pharmacological distribution diagrams: a tool for de novo drug design

BACKGROUND: There is no empirical data available on attitudes concerning AIDS and habits towards HIV infected patients of physicians in general or private practice. In this study results of a self-evaluation are presented. METHODS: 178 physicians working with out-patients in different medical fields were randomly selected for a cross sectional study and interviewed using a standardised questionnaire. RESULTS: 89% think that they are sufficiently informed about AIDS (in the USA 20%). They regarded the risk of infection to be lower than the Anglo-American physicians. They believed there is a lack of interchange of information between colleagues regarding the degree of infectiousness of referred patients. A third of the physicians fear that other patients will go elsewhere if they find out that their physician is treating AIDS patients. 54% would hold special clinic sessions for HIV-patients outside the normal schedule for practice times. 89% believed that HIV patients were partly to blame for their illness. CONCLUSIONS: Although the physicians recognise the problem of HIV-infection, they partly deny the real necessities and facts. A reason for this could be the emotions underlying the general attitude to everything pertaining to HIV-disease. Attitudes to HIV-disease and the dealing with it in daily practice must be considered on the basis of individual emotional motives.     

Prostaglandin E receptor subtypes in mouse osteoblastic cell line

PGE2 is one of the key molecules in the osteoblast. It is the major prostanoid in the bone, and its production is under the control of both systemic and local factors. PGE2 has been reported to have multiple actions in the osteoblast, such as growth promotion and cell differentiation. To better understand the action of PGE2 in the osteoblast, we determined the PGE receptor subtypes in MC3T3-E1, an osteoblastic cell line derived from the normal mouse calvaria. Northern blot analysis revealed that EP1 and EP4 subtypes are expressed in MC3T3-E1. In contrast, EP3 subtype was not detected by either Northern blot analysis or RT-PCR. The contribution of each subtype was evaluated by studying the effects of subtype-specific analogs on osteoblastic function at confluency and 5 days after confluency. An EP1 agonist, 17-phenyl-omega-trinor PGE2, increased DNA synthesis and decreased alkaline phosphatase activity. 11-Deoxy-PGE1, and EP2 and EP4 agonist, decreased DNA synthesis and increased alkaline phosphatase activity at both stages. Butaprost, an EP2-selective agonist, showed effects similar to those of 11-deoxy-PGE1 only at confluency. Another and more differentiated osteoblastic marker, osteocalcin production, was detectable and was stimulated by 11-deoxy-PGE1 only 5 days after confluency. The exposure of these cells to EP1 agonist changed the cell shape to a more fibroblastic appearance. These results indicate that EP1, EP4, and probably EP2 are present in MC3T3-E1 cells; EP1 promotes cell growth, and EP2 and EP4 mediate differentiation of the osteoblast. Furthermore, the decreased response to EP2-specific agonist 5 days after confluency suggests that the expression of PGE receptor subtype is dependent on the stage of osteoblastic differentiation. This is the first report to determine PGE receptor subtypes in the bone.     

Parallel, self-organizing, hierarchical neural networks. II

For pt.I see IEEE Trans. Neural Networks, vol.1, p.167-78 (1990). Parallel, self-organizing, hierarchical neural networks (PSHNNs) involve a number of stages with error detection at the end of each stage, i.e., rejection of error-causing vectors, which are then fed into the next stage after a nonlinear transformation. The stages operate in parallel during testing. Statistical properties and the mechanisms of vector rejection of the PSHNN are discussed in comparison to the maximum likelihood method and the backpropagation network. The PSHNN is highly fault tolerant and robust against errors in the weight values due to the adjustment of the error detection bounds to compensate errors in the weight values. These properties are exploited to develop architectures for programmable implementations in which the programmable parts are reduced to on-off or bipolar switching operations for bulk computations and attenuators for pointwise operations     

Electronic `how things work' articles: two early prototypes

The electronic encyclopedia exploratorium (E³) is a vision of a future computer system-an electronic book describing how thing work. Typical articles in E³ will describe such mechanisms as compression refrigerators, engines, telescopes, and mechanical linkages. Each article will provide simulations, three-dimensional animated graphics that the user can manipulate, laboratory areas that allow a user to modify the device or experiment with related artifacts, and a facility for asking questions and receiving customized, computer-generated English-language explanations. Some of the foundational technology is discussed, focusing on topics in artificial intelligence, graphics, and user interfaces. The initial prototype system and the technical lessons learned from it, as well as the second prototype currently under construction, are described     

Performance of the PAC optical packet network

For multiuser packet communications with unpredictable user demands (e.g., in a local or metropolitan area network), coordination and control of access to the frequency-division multiplexing (FDM) channels are difficult. B. Glance (J. Lightwave Technol., vol.10, pp.1323-1328, Sep 1992) proposed using a simple protection-against-collision (PAC) circuit to solve this media access problem and achieve full optical connectivity. The PAC system has the potential to interconnect hundreds of ports, each transmitting at several gigabits per second. Performance aspects of the PAC optical packet network are discussed here. The delay-throughout performance of this network is analyzed for uniform traffic patterns. The results show that in geographically distributed applications the maximum achievable throughput (normalized to the transmission rate) is typically between 0.4 and 0.5 per channel. In a centralized switch the (normalized) maximum achievable throughput can approach 0.8 per channel     

Planned versus actual duration of drug abuse treatment. Reconciling observational and experimental evidence

The purpose of the study was to evaluate the associations of planned versus actual duration of drug abuse treatment with psychosocial outcomes and drug use at follow-up. A randomized trial was conducted in a modified therapeutic community in which 444 clients were assigned to programs with planned durations of either 3 or 6 months. Outcomes were psychosocial measures assessing changes in mood and in stage of behavior change between admission and exit and return to drug use and patterns of use 2 to 6 months after exit. Planned duration was not associated with any of the outcomes. A longer actual length of stay was, however, associated with greater improvements in the mood variables; lower rates of drug use at follow-up; and, among those using drugs at follow-up, a longer time from exit to first drug use. Intention-to-treat analyses supported these results. Randomized controlled trials are needed to distinguish the effects of planned duration and actual length of stay.     

Electrochemical Aspects of Electroosmotic Dewatering of Clay Suspensions

An attempt is made to elucidate the electrochemical aspects of the electroosmotic dewatering (EOD) of clays as reported in some recent work, especially that on interrupted DC power electroosmotic dewatering published by Rabie, Mujumdar and Weber (2). These authors showed that the dewatering by EOD stops after the DC power has been on for several minutes or hours; on interruption of their power and on short-circuiting of the electrodes, conditions can be created again for some further dewatering by DC power EOD. This discovery, of Rabie et al. is interpreted as a fuel cell effect and it is shown that it affords clues to several other electrochemical strategies for the possible enhancement of the efficiency of the EOD by DC power.

Further, the open circuit potentials observed by Rabie et al. (2) on the interruption of DC power are given an electrochemical interpretation which leads to quantitative estimates in agreement with the experimental values.     

Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects

Safety, local and systemic immunomodulation, and tumor response to treatment with aerosolized natural interleukin 2 (nIL-2) applied five times a day were studied in a Phase I trial in 16 patients with pulmonary malignancies refractory to conventional therapy. The toxicity of inhaled nIL-2 was different from that observed after systemic administration. Reversible airway irritation causing a nonproductive cough represented the dose-limiting toxicity. Mild to moderate reduction of the vital capacity and forced expiratory volume (FEV1) with minor effects on relative FEV1, peak expiratory flow, airway resistance, and PaO2 was experienced by individual patients. In 14 patients suffering from pulmonary metastases due to renal cell cancer, one durable complete response, one partial response, and one mixed response were observed. Inhalation of nIL-2 aerosol resulted in a dose-dependent expansion of pulmonary immunocompetent cells in bronchoalveolar lavage fluid. Posttreatment bronchoalveolar lavage showed an activated lymphocyte phenotype with increased HLA-DR expression. The only systemic biological effect detectable in peripheral blood was a marked increase of soluble interleukin 2 receptor serum levels. We conclude that treatment with aerosolized nIL-2 is an effective means for site-specific immunomodulation and deserves further investigation for the treatment of malignant and inflammatory lung disease.     

The greenhouse effect; Impact upon and the role to be played by construction

The authors highlight several possible ways in which the construction industry could lower present emissions of the greenhouse gas, carbon dioxide. It is an excellent discussion document and is recommended reading.