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The moral tollbooth: a method that makes use of the patent system to address ethical concerns in biotechnology.

Patents granted for biotechnological innovations continue to cause social and ethical dilemmas. For example, much controversy surrounds the patenting of genes that predispose to breast-cancer, and in the USA the debate continues about whether or not stem-cell technology should be accessible to all. In this report, we argue that some of these concerns can be addressed within national patent systems. In particular, we examine the "order public or morality" clause that exists in most national patent procedures. Furthermore, we propose that patents for inventions that present social and ethical questions should be subject to suspension by an independent, transparent, and responsible tribunal made up of specialists in ethics, research, and economics. This suspension should be reversible so that, when the social or ethical concerns have been addressed in an appropriate manner, the suspension can be lifted. Although controversial, such a flexible mechanism would assist governments and industry in enhancing public support for patents in the biotechnology area.

Animals↗

Activities to address antimicrobial resistance in the United States.

Antimicrobials are essential for the prevention and treatment of bacterial infections in humans and animals. Subtherapeutic antimicrobials have been used as growth promoters for >40 years. The subject of antimicrobial resistance is not new but has gained increasing attention due to public-health concerns about multi-resistant pathogenic organisms. Numerous United States' activities do exist to address antimicrobial resistance. A surveillance system (the National Antimicrobial Resistance Monitoring System) was established in 1996 to monitor changes over time in resistance for 17 antibiotics in humans and animals. Educational campaigns have been created to promote the judicious therapeutic use of antimicrobials. Producer groups are developing guidelines for judicious therapeutic antimicrobial use for their prospective species. Basic and applied research programs are being expanded to answer many of the unsolved questions regarding development, persistence, and transmission of antimicrobial resistance. This paper focuses on a federal inter-agency public-health action plan to combat antimicrobial resistance; the plan was released for public comment in 2000. This plan addresses goals and actions to combat antimicrobial resistance in humans and agriculture in four areas: surveillance; research; prevention and control; product development.

Animals↗

Addressing the challenges of transforming laboratory advances into Alzheimer's Disease treatments.

This essay addresses the challenges of clinical trials to develop treatments for Alzheimer's Disease (AD). The issues covered are enrolling subjects, defining clinically meaningful endpoints, and making the claim that a drug slows the progression of the disease. The perspective to address these challenges is that dementia research should embrace a biopsychosocial model for drug development. In this model, the patient and caregiver are seen as interrelated subjects of both treatment and research and outcome measures reflect biomarkers of the disease, the functional morbidity of AD and the distress of caregiving.

Alzheimer Disease↗

Addressing birth in Gaza: using qualitative methods to improve vital registration.

The use of anthropological qualitative methods to validate and improve health surveillance data is demonstrated through an examination of the process of birth registration in Gaza. Theoretically, the importance of understanding the link between historical events and microlevel decision-making is emphasized both in general terms and specifically in the context of the Gaza Strip today. In the course of interviewing a sample of mother/infant pairs selected from a register of births in the Gaza Strip it became evident that 100% of the addresses were incomplete. Using qualitative methods in the form of field visits and interviews with physicians, clerks and nurses, an understanding of the information pathway for birth registration data was developed. It was also established that there was some erroneous recording of birthweight. An intervention was designed which failed to improve the accuracy of addresses but did improve the recording of birthweight.

Adolescent↗

Building a feminist theoretical framework for screening of wife-battering: key issues to be addressed.

The purpose of this paper is to identify key questions which must be addressed in developing a woman-centred, that is feminist, theoretical framework for screening for wife battering in health settings. The health sector has not had a positive history in addressing women's health holistically or in terms of the social context of women's lives. This is notable in relation to the issue of wife battering, where attention is recent but growing and responses have been varied. On the other hand, violence against women is one of the greatest threats to their health and, therefore, it can be argued that the health sector has a major role to play in ending this violence. With the recent efforts within the health sector, a great deal has been accomplished; we have some consensus on what is an appropriate protocol for and the roles of health care providers. We are also making progress in developing training programs. Several things are still lacking an understanding of the systemic barriers to promotion of and participation in screening; sufficient program evaluations; sufficient attention to issues of diversity among women; and, a theoretical framework for practice which links these together.

Adult↗

Addressing women's concerns about weight gain due to smoking cessation.

Specific concerns about weight gain following smoking cessation inhibit attempts to quit smoking, especially in women. However, adjunct interventions to prevent weight gain after cessation have generally been successful only in attenuating, rather than preventing, weight gain. More aggressive weight control adjuncts may be necessary to prevent cessation-induced weight gain. On the other hand, weight control programs have not been found to improve long-term smoking abstinence and, in fact, may actually impede abstinence, necessitating a search for alternative approaches to addressing weight concerns. Since the typical amount of weight gain is essentially trivial from a health standpoint, particularly when compared with the health benefits of quitting smoking, the most appropriate clinical strategy may be to combat the weight concerns themselves rather than the weight gain. A second alternative approach is to focus all treatment efforts on smoking cessation alone, to avoid placing excessive burdens on participants resulting from attempting simultaneous changes in multiple health behaviors (i.e., smoking and those related to weight). The rationales for these three clinical approaches to addressing concerns about weight gain-more effective weight control, direct reduction in weight concerns by cognitive-behavioral treatment, and smoking cessation only-are presented, followed by descriptions of the adjunct treatments based on these approaches currently being evaluated in a clinical outcome study with women trying to quit smoking.

Body Image↗

Rapid identification of biological warfare agents using an instrument employing a light addressable potentiometric sensor and a flow-through immunofiltration-enzyme assay system.

An instrument employing a light addressable potentiometric sensor and a flow-through immunofiltration-enzyme assay system has been developed for the rapid and specific identification of biological warfare (BW) agents. The system has been designed to assay for up to eight agents simultaneously and provides an indication of the absence or presence of a threat within 15 min. Parameters affecting the mixing of the reagents within the instrument's fluidic lines were investigated and optimized. Measurements of blank samples and samples containing Bacillus subtilis spores in the concentration range of 10(4) to 10(6) cfu/ml indicate the limit of detection (LOD) is 3 x 10(3) cfu/ml for B. subtilus. Although the LOD is higher than that of several technologies currently under development, this instrument offers an immediate interim approach for addressing the need to rapidly detect biological warfare agents in the field.

Bacillus subtilis↗

Derivatives of 17-(2-methylallyl)-substituted noroxymorphone: variation of the delta address and its effects on affinity and selectivity for the delta opioid receptor.

In an effort to establish the importance of the N-(2-methylallyl) substituent in the noroxymorphone series, several derivatives have been synthesized, retaining that N-substituent and modifying the delta address moiety. A few compounds showed moderate binding affinity and selectivity for the delta receptor; none displayed a pharmacological profile as exceptional as N-(2-methylallyl)noroxymorphindole. A second study showed that 3-O-methylation of all derivatives decreases binding affinity. The present results indicate that only a combination of the N-(2-methylallyl) group and an indole delta address provided high selectivity for the delta receptor.

Oxymorphone↗

Addressing semen loss concerns: towards culturally appropriate HIV/AIDS interventions in Gujarat, India.

A situation analysis of sexual networking and sexual health in an industrial area of Gujarat, India, identified anxiety about masturbation and other semen loss concerns as major preoccupations among young men. This paper describes how the Deepak Charitable Trust addressed these concerns in their HIV prevention programme for young men aged 15 to 30. Flowcharts were used as participatory learning tools and to obtain data on the perceived consequences of masturbation, both before and after intervention activities. Research was also done on the relation between semen-related anxieties and sexual risk behaviour by DCT and two other NGOs among young men engaging in unsafe sexual behaviour. DCT advocates addressing masturbation and other semen loss concerns in all sexual health campaigns in South Asia, based on the magnitude of these concerns, their potential to confound syndromic management of STIs and their significance as an idiom of psychosocial distress. Masturbation and associated anxieties about sexual performance are seen as health issues and discussed as such by the programme. There is immediate identification among young men, whether or not they are already sexually active, and it provides an excellent entry point for sexual health and safer sex education. The community response to these efforts has been entirely positive.

Adolescent↗

Will the pill make me sterile? Addressing reproductive health concerns and strategies to improve adherence to hormonal contraceptive regimens in adolescent girls.

UNLABELLED: PAPER OBJECTIVE: This paper is designed to help clinicians understand the relationship between hormonal contraceptive side effects and the potential development of general and reproductive health concerns that can impact on adherence to hormonal contraception. By understanding the concerns raised by young women, we can then make our counseling more specific to the factors that affect compliance in this population. DESIGN: Studies that specifically addressed hormonal contraceptive compliance, side effects, and method selection in adolescents and young women were chosen for this paper. All articles were from peer-reviewed journals. Medline-Ovid articles from 1980-2000 were used with the following search keywords: Contraception, Patient Compliance, Hormonal Contraception, Oral Contraceptive Pills, Norplant, Depo Provera, and Adolescents. DATA SYNTHESIS: The general public has many concerns about the safety of hormonal contraception. The development of side effects, especially those that are menstrual-related, seem to cause adolescents and young women to feel that their general and reproductive health is being threatened. CONCLUSIONS: Hormonal contraceptive counseling should include 1) explaining, in a nontechnical manner, how these methods work; 2) addressing negative information the patient has heard about the methods; 3) providing factual information about cancer risks, blood clots, and other general health concerns; 4) discussing the potential side effects and what each means to her health; 5) asking specifically about possible reproductive health worries, especially in light of the menstrual irregularities that may occur; and 6) assuring the patient that she should always feel free to share her concerns and worries with you, the provider.

Adolescent↗

Addressing patients' emotional and spiritual needs.

BACKGROUND: A comprehensive, systematic literature review and original research were conducted to ascertain whether patients' emotional and spiritual needs are important, whether hospitals are effective in addressing these needs, and what strategies should guide improvement. METHODS: The literature review was conducted in August 2002. Patient satisfaction data were derived from the Press Ganey Associates' 2001 National Inpatient Database; survey data were collected from 1,732,562 patients between January 2001 and December 2001. RESULTS: Data analysis revealed a strong relationship between the "degree to which staff addressed emotional/spiritual needs" and overall patient satisfaction. Three measures most highly correlated with this measure of emotional/spiritual care were (1) staff response to concerns/complaints, (2) staff effort to include patients in decisions about treatment, and (3) staff sensitivity to the inconvenience that health problems and hospitalization can cause. DISCUSSION: The emotional and spiritual experience of hospitalization remains a prime opportunity for QI. Suggestions for improvement include the immediate availability of resources, appropriate referrals to chaplains or leaders in the religious community, a team dedicated to evaluating and improving the emotional and spiritual care experience, and standardized elicitation and meeting of emotional and spiritual needs. Survey data suggested a focus on response to concerns/complaints, treatment decision making, and staff sensitivity.

Chaplaincy Service, Hospital↗

Individually addressable gel-integrated voltammetric microelectrode array for high-resolution measurement of concentration profiles at interfaces.

The application of a novel voltammetric probe, based on an individually addressable gel-integrated microelectrode array (IA-GIME), for real-time, high-spatial resolution concentration profile measurements at interfaces is described. Reliability and validity of steep metal concentration gradients obtained with this novel system have been demonstrated by performing systematic tests at well-controlled liquid-liquid and liquid-solid interfaces. The liquid-liquid interface was formed by two layers of aqueous solutions with different components; only one layer contained trace metal ions (Pb(II) and Cd(II)); the individually addressable microelectrode array was placed at the interface of the liquid-liquid system; the concentration profiles were recorded as function of time; and the effective diffusion coefficients were calculated. The liquid-"solid" interface was formed from an aqueous solution layer overlying a bed of silica particles saturated with an aqueous solution. The sensor array has been used to monitor the diffusion processes of Tl(I) or Pb(II) from the liquid phase to the "solid" phase. The influences of porosity, geometry of the porous media, and complexation between metal ion and silica, on the diffusion processes, have been studied. All these results show that correct diffusion profiles of metal ions at interfaces can be obtained with 200-microm resolution with the IA-GIME. They also demonstrate that, for measurements in "solid" phase, the aforementioned factors must be considered carefully for correct calibration of any electrodes and the gel-integrated microelectrodes are unique tools to enable calibration of the sensors with synthetic solutions.

Journal Article↗

Spatially addressed synthesis of amino- and amino-oxy-substituted 1, 3,5-triazine arrays on polymeric membranes.

Effective spatially addressed parallel assembly of trisamino- and amino-oxy-1,3,5-triazines was achieved by applying the SPOT-synthesis technique on cellulose and polypropylene membranes. In addition to developing a suitable linker strategy and employing amines and phenolate ions as building blocks, a highly effective microwave-assisted nucleophilic substitution procedure at membrane-bound monochlorotriazines was developed. The 1,3, 5-triazines obtained could be cleaved in parallel from the solid support by TFA vapor to give compounds adsorbed on the membrane surface in a conserved spatially addressed format for analysis and screening. The reaction conditions developed were employed for the synthesis of 8000 cellulose-bound 1,3,5-triazines which were probed in parallel for binding to the anti-transforming growth factor-alpha monoclonal antibody Tab2 in order to identify epitope mimics.

Amines↗

Binding of norbinaltorphimine (norBNI) congeners to wild-type and mutant mu and kappa opioid receptors: molecular recognition loci for the pharmacophore and address components of kappa antagonists.

Molecular modifications of both the kappa opioid antagonist norbinaltorphimine (norBNI, 1) and the kappa receptor have provided evidence that the selectivity of this ligand is conferred through ionic interaction if its N17' protonated amine group (an "address") with a nonconserved acidic residue (Glu297) on the kappa receptor. In the present study, we have examined the effect of structural modifications on the affinity of norBNI analogues for wild-type and mutant kappa and mu opioid receptors expressed in COS-7 cells. Compounds 2, 3, and 7, which have an antagonist pharmacophore and basic N17' group in common with norBNI, retained high affinity for the wild-type kappa but exhibited greatly reduced affinity for mutant kappa receptors (E297K and E297A). Modification of the phenolic or N-substituent groups of the antagonist pharmacophore (4 and 5) or removal of basicity at the address N17' center (6) led to greatly reduced affinity for the wild-type and mutant receptors. The reduced affinity upon modification of the kappa receptor is consistent with the ionic interaction of the protonated N17' group of kappa antagonists (1-3, 7) with the carboxylate group of E297 at the top of TM6. This was supported by the greatly enhanced affinity of compounds 1-3 for the mutant mu receptor (K303E), as compared to the wild-type mu receptor, given that residue K303 occupies a position equivalent to that of E297 in the kappa receptor. In view of the high degree of homology of the seven TM domains of the kappa and mu opioid receptors, it is suggested that the antagonist pharmacophore is bound within this highly conserved region of the kappa or mutant mu receptor and that an anionic residue at the top of TM6 (E297 or K303E, respectively) provides additional binding affinity.

Amino Acid Substitution↗

Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus.

The delta-selective opioid antagonist naltrindole (NTI), as well as the kappa-selective opioid antagonists norbinaltorphimine (norBNI) and 5'-guanidinonaltrindole (GNTI), are derived from naltrexone, a universal opioid antagonist. Previous studies have indicated that extracellular loop III is the key region for discrimination by naltrexone-derived selective ligands between the delta, mu, and kappa opioid receptor types. It has been proposed that selective ligands could bind to all three receptor types if the appropriate portions of the extracellular loops were eliminated. To investigate this possibility, several single-point mutant opioid receptors have been generated with the aim of conferring enhanced affinity of selective ligands for their nonpreferred receptor types. Mutations were made in all three types of opioid receptors with the focus on two positions at the extracellular end of transmembrane regions (TM) VI and VII. It was found that the delta-selective NTI could bind both mu and kappa receptors with significantly enhanced affinity when an aromatic residue in TM VII was replaced with alanine (mu[W318A] and kappa[Y312A]). Similarly, kappa-selective antagonists, norBNI and GNTI, showed enhanced affinity for the mu[W318A] mutant and for both mu and delta receptors when a glutamate residue was incorporated into the extracellular end of TM VI (mu[K303E] and delta[W284E]). These results demonstrate that naltrexone-derived selective ligands achieve their selectivity via a combination of enhanced affinity of the address for a particular subsite along with loss of affinity due to steric interference at nonpreferred types. The results reveal key residues in the "address" recognition locus that contribute to the selectivity of opioid ligands and support the hypothesis that recognition of the naltrexone moiety is essentially the same for all three receptor types.

Amino Acid Sequence↗

Function of negative charge in the "address domain" of deltorphins.

Deltorphins A, B, and C exhibit high delta-affinities (Ki = 0.12-0.31 nM) and very high delta-receptor binding selectivities (Ki mu/Ki delta = 1800-4100). A study of the delta-receptor binding properties of 15 deltorphin analogues focused primarily on the influence of the anionic group in the C-terminal tetrapeptide. Amidation of the beta-carboxyl groups of [Asp7], [Glu4], or [Asp4] in deltorphins A, B, and C, respectively, yielded peptides with enhanced mu-receptor affinities and minor changes in delta-affinities (Ki delta = 0.20-0.65 nM), but 5-8-fold diminished delta-selectivities. A free C-terminal carboxyl group markedly reduced delta-affinities and decreased delta-selectivities 6-11-fold; thus, the C-terminal amide group critically facilitates delta-affinity. Modifications in the anionic charged group or hydrophobic residues in the C-terminal tetrapeptide address domain of deltorphin A altered spatial distributions critical for delta-affinity and selectivity; e.g., [Nle6]deltorphin A enhanced mu-affinity and lowered delta-selectivity by two-thirds; the progressive, step-wise repositioning of Asp in deltorphin C (from position 4 to 7) was accompanied by linear decreases in delta-affinities and -selectivities, and increased mu-affinities of these peptides; enhancement of the charge density to -2, in [Asp6, Asp-OH7]deltorphin A, decreased delta-affinity and -selectivity, while [Asp4,5,His7]deltorphin A bound to neither mu- nor delta-sites. These results demonstrate that while an anionic group may occasionally facilitate high delta-receptor affinity, it represents an absolute requirement for the high delta-binding selectivity of these peptides. The locations of the charged groups relative to hydrophobic residues in the address domain of the peptide are also critical determinants for both delta-affinity and -selectivity.

Animals↗

Synthesis of 7-arylmorphinans. Probing the "address" requirements for selectivity at opioid delta receptors.

Through arylation of 6-keto opiates with diaryliodonium iodide, a series of 7-aryl opiates (3-8) have been prepared in an effort to investigate the effect of conformational mobility of the delta "address" moiety on opioid agonist and antagonist potencies. Evaluation of the ligands in the mouse vas deferens and guinea pig ileum preparations revealed that they were less potent and less selective than the conformationally constrained ligands, naltrindole (1, NTI) and 7-(spiroindanyl)oxymorphone (2, SIOM), at delta opioid receptors. It is concluded that the coplanarity of the address moiety with the C ring of the morphinan structure enhances delta antagonist potency and selectivity.

Animals↗

Sentence comprehension is mediated by content-addressable memory structures.

Studies of working memory demonstrate that some forms of information are retrieved by a content-addressable mechanism (McElree & Dosher, 1989; McElree, 1996, 1998), whereas others require a slower search-based mechanism (McElree & Dosher, 1993). Measures of the speed and accuracy of processing sentences with filler-gap dependencies demonstrate that the probability of maintaining a representation of a filler item decreases as additional material is processed, but that the speed with which a preserved representation is accessed is unaffected by the amount of interpolated material. These results suggest that basic binding operations in sentence comprehension are mediated by a content-addressable memory system.

Cognition↗