Drug design for ever, from hype to hope.

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.

Alpha4 integrin binding interfaces on VCAM-1 and MAdCAM-1. Integrin binding footprints identify accessory binding sites that play a role in integrin specificity.

Integrins are a family of heterodimeric adhesion receptors that mediate cellular interactions with a range of matrix components and cell surface proteins. Vascular cell adhesion molecule-1 (VCAM-1) is an endothelial cell ligand for two leukocyte integrins (alpha4beta1 and alpha4beta7). A related CAM, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is recognized by alpha4beta7 but is a poor ligand for alpha4beta1. Previous studies have revealed that all alpha4 integrin-ligand interactions are dependent on a key acidic ligand motif centered on the CAM domain 1 C-D loop region. By generating VCAM-1/MAdCAM-1 chimeras and testing recombinant proteins in cell adhesion assays we have found that alpha4beta1 binds to the MAdCAM-1 adhesion motif when present in VCAM-1, but not when the VCAM-1 motif was present in MAdCAM-1, suggesting that this region does not contain all of the information necessary to determine integrin binding specificity. To characterize integrin-CAM specificity further we measured alpha4beta1 and alpha4beta7 binding to a comprehensive set of mutant VCAM-1 constructs containing amino acid substitutions within the predicted integrin adhesion face. These data revealed the presence of key "regulatory residues" adjacent to integrin contact sites and an important difference in the "footprint" of alpha4beta1 and alpha4beta7 that was associated with an accessory binding site located in VCAM-1 Ig domain 2. The analogous region in MAdCAM-1 is markedly different in size and sequence and when mutated abolishes integrin binding activity.

Evaluation of the home pad test in the investigation of female urinary incontinence.

OBJECTIVE: To evaluate the use of the home pad test in the management of patients with urinary dysfunction with reference to feasibility, normal data, reproducibility, compliance and accuracy when compared to video urodynamics. DESIGN: A prospective study to determine 1. the accuracy of weighing pads by healthcare workers compared to weighing by patients with a spring balance; 2. the effects of evaporation; 3. the pad weight increase in continent women; 4. the compliance over 194 tests in terms of acceptability and feasibility; 5. the reproducibility in 112 women for the 24 h and 48 h tests, 6. the comparison with video urodynamic studies in 149 patients. SETTING: A London teaching hospital. MAIN OUTCOME MEASURES: Coefficient of variation and mean deviation analysis were employed to determine the accuracy of measurement. Percentage changes in standardised wet pad weights over a period of 8 weeks were used to determine the rate of weight loss due to evaporation. The percentage of patients completing the test satisfactorily was documented. The increase in the weights of all pads worn during the test period was measured in continent volunteers and incontinent patients. Video urodynamic diagnoses were used as the Gold Standard for comparison. RESULTS: Twelve perineal pads were weighed by 15 healthcare workers with a resulting coefficient of variation equal to 1.55% (standard error = 0.09%). The mean deviation between patient-measured pad weights and staff-measured weights was 49% (SD = 132%). Pads wetted with saline showed no difference in weight after 1 week and less than 5% change in weight after 8 weeks, with the upper 95% confidence limit of less than 10% loss. The mean pad weight increase over 48 h in continent women was 7.13 g (SD = 4.32 g) giving a 95% upper confidence level of less than 15 g. Compliance was reasonably high with 161 (83%) carrying out the test perfectly. Test-retest analysis of the 24 h and 48 h tests showed a strong relationship with correlation coefficients of 0.90 and 0.94 respectively. The reproducibility was also good, with differences as a percentage of the mean between the first and second test being 6.9% and 1.6% for the 24 h and 48 h tests respectively. There was good concordance when the urodynamic study data was compared with pad weight data in terms of incontinence compared with no incontinence (kappa = 0.65), but a high false positive rate was detected for the pads. When eight of these patients with a false positive pad test had repeat video urodynamic studies, six were found to have detrusor instability on the second study. CONCLUSIONS: The home pad test combined with frequency volume chart documentation is an easy test to perform. It is quite robust and reasonably reproducible. This test should be added to complement the routine urodynamic tests and may have a role in detecting occult detrusor instability.

Obstetric outcome of Bangladeshi women in east London.

OBJECTIVE: To study the obstetric outcome of women of Bangladeshi origin in comparison with the white caucasian population in East London. DESIGN: A retrospective study of 16718 pregnancies over a five year period (1987-1991). SETTING: An East London teaching hospital district. SUBJECTS: Six thousand four hundred and sixty Bangladeshi women compared with 7592 white caucasian women. MAIN OUTCOME MEASURES: Maternal: antenatal complications; induction and augmentation rates; analgesia and anaesthesia; instrumental delivery and caesarean section rates; third stage complications. Fetal: gestation and weight at birth; perinatal mortality rates. RESULTS: The following statistically significant findings were noted: Bangladeshi women had a longer reproductive age span and were of greater parity including grand multiparity. They suffered fewer antenatal complications except for gestational diabetes. They had lower induction rates and, among the parous group, lower augmentation rates. During labour they required less analgesia but more commonly had general anaesthesia for caesarean section deliveries. They required instrumental delivery less often but there was no difference in overall caesarean section rate for the two groups. However, overall Bangladeshi women had a lower elective caesarean section rate, although parous Bangladeshi women had a higher emergency section rate. In the third stage there were no differences in the complication rates for the nulliparous women, however the parous Bangladeshi women had a higher postpartum haemorrhage rate and a lower perineal repair rate consistent with their higher parity. Whilst preterm births were more common in Bangladeshi women, significant prematurity (less than 28 weeks gestation) was less common. Similarly, although Bangladeshi babies weighed less at birth, they had fewer babies weighing less than 1500 grammes. There was no statistically significant difference in the perinatal mortality rate between the two groups, being 8.1 per thousand births overall. Whilst there was a statistically insignificant decline in death rates over the five-year period, between the groups there was no consistent difference. CONCLUSION: Pregnant Bangladeshi women in East London constitute a relatively high parity, low risk population who have less obstetric intervention and yet manage an equivalent (or better) perinatal outcome compared to their white caucasian neighbours.

The relative effectiveness of four methods of teaching practical scientific skills to secondary school students.

The investigation compares the effectiveness of four methods of teaching students how to perform two practical scientific skills. The methods commonly used combinations of four different modes of communication. Method W uses written instructions only. Method WG has these written instructions supplemented with graphics. Method WGS adds spoken instructions to the combination used in Method WG, and Method WGSD also includes a video-recorded demonstration of the practical task. After teaching random groups (N = 20) of students aged 14-15 years with one of the methods, their effectiveness was assessed in terms of the students' performance on test exercises which required the students to carry out these tasks. The results showed that the methods involving the use of spoken instructions (i.e. WGS and WGSD) were significantly worse than those that did not use spoken instructions. The use of graphics also had no significant beneficial effect, and the demonstration had a significant positive effect only in one task.

Clinical comparison of 10 percent and 25 percent intravenous sodium fluorescein solutions.

Sodium fluorescein solutions, 3 ml of 25% solution and 5 ml of 10% solution, were compared with a double-blind crossover method in a group of 41 normal volunteers and in a group of 42 patients who had diverse ophthalmic disorders. Following injection of the solutions into the antecubital vein, visualization, serial fluorescein angiograms, and five-minute phase angiograms were studied and compared. The untoward reactions reported in both studies were of types usually associated with sodium fluorescein, the most common of which was a mild, transient nausea. On the basis of our results, there is no significant difference in the incidence and severity of adverse reactions between the 10% and 25% solutions. In the volunteer study, the 25% solution was significantly superior in visualization and paired comparison (P less than .001) in the patient study, the 25% solution was significantly superior in angiogram quality (P less than .01), five-minute phase angiogram (P less than .05), and paired comparison (P less than .005). The overall superiority of the 25% concentration in a 3-ml volume was demonstrated both subjectively and objectively in the volunteer study and in the patient study.

The influence of secondary depth cues on the understanding by Nigerian schoolboys of spatial relationships in pictures.

The ability of 105 Nigerian schoolboys to interpret pictures three-dimensionally was studied as a function of changing the number of depth cues on moving from monochrome photographs incorporating the effects of shadow, through fully cued line drawings, to line drawings containing only elevation cues. The experiment also investigated the effects of different amounts of previous formal training in technical drawing on performance in these tasks. The results showed a significant increase in performance as the number of depth cues increased above that contained in the minimum cued line drawings. However, the difference between the effects of fully cued line drawings and the photographs was not significant. Neither the main nor interaction effects relating to levels of formal training in technical drawing were significant.

The effects of chronological age on the relationship of intelligence and academic achievement with extraversion and neuroticism.

This study examines the possibility that the relationships of intelligence and academic achievement with both extraversion and neuroticism may vary with chronological age. A sample of 741 students in the 15-19 age group worked through a battery of four tests, two of which were tests of intelligence and two tests of achievement in chemistry. The nature of the relationships between performance on these tests and measures of extraversion, neuroticism and chronological age were then expressed as multiple regression equations. The results whoed a consistently different pattern of significant relationships for both extraversion and neuroticism with the achievement tests on the one hand and with the intelligence tests on the other. Only the performance on the two achievement tests depended upon an interaction between extraversion and chronological age. There were no such interactions involving neuroticism and chronological age.