Investigation of the ways in which patients' reports of their satisfaction with healthcare are constructed

A characteristic feature of patient satisfaction research is the consistently high level of satisfaction recorded. More reliable and relevant inquiry tools are constantly being developed, but underlying psychological and social pressures that could promote such a consistent and undiscriminating response have been little investigated. Williams et al. (1998) explored the phenomenon and concluded that, by considering issues of duty and culpability, patients could make allowances for poor care, and avoid evaluating it negatively. Their study was in community mental health. This study follows up their work within elective orthopaedic surgery, and investigates the pressures promoting such apparent transformation of opinion. Using a longitudinal design, and in-depth qualitative interviews, the patient's process of reflection was explored. Three psycho-social pressures were identified that appear to work together to make the transformation of opinion almost the default process. They are: the relative dependency of patients within the healthcare system; their need to maintain constructive working relationships with those providing their care; and their general preference for holding a positive outlook. It is suggested that, while it is the patient's prerogative to re-interpret the quality of their care positively, it is not the prerogative of the inquirer to accept this re-interpretation as representative of the patient's experience. Methods of inquiry are needed which access something of patients' development of opinion, and thereby something of their initial, often more negative, untransformed responses to their healthcare experiences.     

Reliability of the IOLMaster in measuring corneal power changes after photorefractive keratectomy

PURPOSE: To test the accuracy of the IOLMaster (Carl Zeiss) in detecting corneal power changes after photorefractive keratectomy (PRK). SETTING: Department of Ophthalmology, 2nd University of Naples, Naples, Italy. METHODS: Two hundred twenty-five consecutive eyes that had PRK (mean -5.13 diopters [D] +/- 2.98 [SD] [range +0.25 to -16.25 D]) were analyzed. The data included preoperative and postoperative (1, 3, and 6 months) subjective refraction and computerized keratometry. Statistical analysis was performed to determine the correlation between the changes in the subjective refraction at the corneal plane and the changes in keratometry. RESULTS: The mean difference between the changes in refraction and the measured corneal changes was 0.75 +/- 1.13 D (range -3.84 to +7.68 D) at 1 month, 0.92 +/- 1.10 D (range -0.87 to +7.93 D) at 3 months, and 0.75 +/- 0.98 D (range -1.70 to +3.85 D) at 6 months. The difference was significant (P<.001). CONCLUSION: Automated keratometry provided by the IOLMaster did not accurately reflect the effective refractive changes after PRK, particularly in eyes that had a high dioptric treatment.     

Prevalent use of complementary and alternative medicine by patients with inflammatory eye disease

AIM: To study complementary and alternative medicine (CAM) use in patients who suffer from inflammatory eye disease. METHODS: Current and previous use of CAM was determined by face-to-face interviews of consecutive patients attending a university-based tertiary-referral inflammatory eye disease clinic during a 3-month period. Additional sociodemographic and clinical information was obtained by review of clinical records. RESULTS: Of the 89 eligible patients who were interviewed, 37 (42%) reported using CAM for the specific purpose of improving their eye condition. Most commonly used CAM included vitamin preparations (n = 13), herbal medicines (n = 10), prayer (n = 15) and acupuncture (n = 9). Multiple forms of CAM were used by one third of patients. Female gender (p = 0.05), a higher rating of occupational prestige (p = 0.05) and the diagnosis of uveitis rather than another form of inflammatory eye disease (p = 0.04) were significantly associated with reporting of current or past use of CAM. Most patients who used CAM considered that these therapies were benefiting their ocular condition, and few adverse events were reported. Sixteen percent of patients cited physician resources as a source for therapeutic information about CAM. CONCLUSIONS: Use of CAM is common among patients with inflammatory eye diseases. Because CAM may influence the course of disease, cause adverse effects, and interact with conventional immunosuppressive treatment, physicians should routinely question patients with these diagnoses regarding the use of such therapies.     

Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones

1. The effects of donepezil, one of the most common cholinesterase inhibitors used for treatment of Alzheimer's disease, were studied on nicotinic receptors (nAChRs)-mediated postsynaptic currents, in dopaminergic neurons of the substantia nigra pars compacta, using the patch-clamp recording technique in slice preparations. 2. Donepezil (10-100 microM) selectively and reversibly depressed nicotine currents, induced by brief puffer pulses, through a glass micropipette positioned above the slice. 3. The peak amplitude fading of the responses generated by repeated test applications of low doses of nicotine was accelerated by donepezil, while it slowed the recovery of nicotine currents after a large, desensitising, dose of the same agonist. 4. Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent. 5. Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine-induced currents. The data indicated direct effect on nAChR, independent from the activity of donepezil as cholinesterase inhibitor.     

Design, synthesis, and evaluation of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as inhibitors of poly(ADP-ribose) polymerase

The design, synthesis, and biological evaluation of potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are reported. A novel series of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones were designed using a combination of protein structure-based drug design, molecular modeling, and structure-activity relationships (SAR). These novel submicromolar inhibitors possess a tricyclic ring system conformationally restricting the benzamide in the preferred cis orientation. The compounds were designed to optimize space-filling and atomic interactions within the NAD+ binding site of PARP-1. Previously described and newly adapted methods were applied to syntheses of these tricyclic inhibitors. Various modifications were made to the diazepinoindolones at the 6- and 7-positions in order to study this region of the active site and optimize noncovalent interactions. The electron density of derivative 28 bound to chicken PARP-1 revealed that the oxime makes a tight hydrogen bond with the catalytic gamma-carboxylate of glutamic acid (Glu) 988 in accordance with our original designs and models. Most of the compounds have been evaluated for inhibition of human PARP-1. Selected inhibitors were also tested for the ability to potentiate the cytotoxic effect of the DNA-damaging agent Topotecan.     

Cytotoxic alpha-halogenoacrylic derivatives of distamycin A and congeners

The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. We now report and discuss the synthesis, the in vitro and in vivo activities, and some mechanistic features of alpha-halogenoacrylamido derivatives of distamycin A. The final result of this work was the selection of brostallicin 17 (PNU-166196). Brostallicin, presently in phase II clinical trials, shows a broad spectrum of antitumor activity and an apoptotic effect higher than distamycin derivative tallimustine. An important in vitro toxicological feature of brostallicin is the very good ratio between myelotoxicity on human haematopoietic progenitor cells and cytotoxicity on tumor cells, in comparison with clinically tested DNA minor groove binders. A peculiarity of brostallicin is its in vitro reactivity in the DNA alkylation assays only in the presence of glutathione. Moreover brostallicin's antitumor activity, both in in vitro and in vivo tumor models, is higher in the presence of increased levels of glutathione/glutathione-S-tranferases. These findings contribute to the definition of brostallicin as a novel anticancer agent that differs from other minor groove binders and alkylating agents for both the profile of activity and the mechanism of action and to classify the alpha-bromoacrylamido derivatives of distamycin as a new class of cytotoxics. Moreover, due to its interaction with glutathione, brostallicin may have a role for the tailored treatment of tumors characterized by constitutive or therapy-induced overexpression of glutathione/glutathione-S-tranferase levels.     

Structure-affinity relationship study on N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides, a new class of 5-hydroxytryptamine7 receptor agents

A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides was prepared and their affinity for serotonin (5-hydroxytryptamine, 5-HT) 5-HT7, 5-HT(1A), and 5-HT(2A) receptors was measured by in vitro binding assays. In relation to 5-HT7 receptor affinity, receptor binding studies indicated that (i) the optimal alkyl chain length was five methylenes, (ii) an unsubstituted 1,2,3,4-tetrahydronaphthalenyl nucleus was preferred, and (iii) the substitution pattern of the aryl ring linked to the piperazine ring played a crucial role. Several compound with high affinity for 5-HT7 receptors were identified. Among them, 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (28), 4-(2-acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (34), 4-(2-methylthiophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (44), 4-(2-hydroxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (46), and 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT7 receptor-mediated relaxation of substance P-induced guinea pig ileum contraction. Compounds 28, 44, and 49 behaved as full agonists and compound 34 as a partial agonist, whereas derivative 46 acted as an antagonist. Among the compounds presented here, it emerged that 44 was identified as a potent 5-HT7 receptor agonist (Ki = 0.22 nM, EC50 = 2.56 microM), endowed with selectivity over 5-HT(1A) and 5-HT(2A) receptors (200-fold and >1000-fold, respectively).     

Reliable high-throughput functional screening with 3-FABS

An NMR method called 3-FABS has extended the capabilities of NMR, enabling rapid, efficient and reliable high-throughput functional screening for the identification of inhibitors and for measuring their 50% mean inhibition concentration (IC(50)) with accuracy. The substrate is tagged with a CF(3) moiety and (19)F NMR spectroscopy is used for the detection of the substrate and product components. We provide comprehensive insight into 3-FABS, a discussion of its strength and weakness when compared with other HTS techniques and a presentation of some of its applications to the screening of different enzymes and to multiple screening.     

Toward the pharmacogenomics of cystic fibrosis--an update

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasians, with a frequency of approximately 1 in 3000 live births. The mutated gene is a defective chloride channel in epithelial cells, named cystic fibrosis transmembrane conductance regulator (CFTR). Several different protocols for the scanning of the entire gene have aided molecular diagnosis and improved our understanding of the disorder's pathophysiology, but also showed the disease's complexity. Therefore, CF phenotype remains difficult to predict from CFTR mutation data alone: several studies have suggested that additional genes could modulate its clinical outcome. Gene replacement therapy is still far from being used in patients with CF, mostly due to the difficulties with targeting the appropriate cells. In this review, we summarize recent advances, both in the pharmacological and gene therapy field, aimed for the treatment of the disease.