Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure.

Purine nucleotides transduce cell membrane receptor responses and modulate ion channel activity. This is accomplished through conformational change in the structure of nucleotides and cell membrane associated proteins. The aim of this study is to enhance our understanding of nucleotide dependence in regard to signal transduction events, drug action and pharmacological promiscuity. Nucleotides and ligand structures regulating Gα protein subunits, voltage- and ligand-gated ion channels are investigated for molecular similarity using a computational program. Results differentiate agonist and antagonist structures, identify molecular similarity within nucleotide and ligand structures and demonstrate the potential of ligands to regulate nucleotide conformational change. Relative molecular similarity within nucleotides and the ligands of the major receptor classes provides insight into mechanisms of receptor and ion channel regulation. The nucleotide template model has some merit as an initial screening tool in the study and comparison of drug and hormone structures.

Exploratory study to evaluate the provision of additional midwifery support to teenage mothers.

OBJECTIVE: To evaluate the provision of psychosocial interventions of potential benefit to pregnant teenage women. STUDY DESIGN: Pre-test/post-test, controlled, experimental design. METHODS: One hundred and sixty-four pregnant teenage women received usual midwifery care or usual midwifery care plus additional psychosocial support. Four outcomes were measured at baseline and 4 weeks after delivery: self-esteem (Rosenberg Self-Esteem Scale), physical activity (International Physical Activity Questionnaire), social support (Short Form Social Support Questionnaire) and smoking behaviour (yes/no). RESULTS: At follow-up, there were no significant differences in any of these outcomes between the 65 women in the intervention group and the 64 women in the control group who completed both assessments (mean age 17.5 years). There was no difference in use of National Health Service (NHS) services, but the intervention group made greater use of non-NHS services, such as family planning or help with housing or benefits problems. CONCLUSION: The very low self-esteem of the women in the study may indicate that the intervention was not sufficiently robust to impact on mental health and lifestyle, although a longer follow-up may be needed to confirm this. Discrepancy in the evidence provided by formal and informal data suggests that project benefits may have been more evident if the evaluation had included a qualitative element to address the complexity of the client group and intervention.

Diagnostic trends in autistic spectrum disorders in the South Wales valleys.

This study provides an analysis of the diagnostic trends in autistic spectrum disorder (ASD) for children aged under 17 years in the Rhondda and Taff Ely districts of South Wales. In the period 1988-2004, 336 children received a diagnosis of ASD and represent the case registry data of one community paediatric team. For the period 1994-2003, the caseload of 267 comprised Asperger (58%), Kanner (20%) and ;other forms' of autism (22%). In comparison to the previous 5 year period, diagnosis of ASD in 1999-2003 increased for Asperger (2.9 fold) and ;other forms' (4.4) but decreased for Kanner autism (0.69). Male:female gender ratios and age at diagnosis fell for all subcategories of ASD. Prevalences per 10,000 children born in Rhondda Taff Ely are ASD 61.2, Asperger 35.4, Kanner autism 12.7, and 'other forms' 13.0. Detected prevalences and trends for ASD are in line with national standards and do not show an increase for Kanner autism.

Voltage-gated Na+ channel ligands and ATP: relative molecular similarity and implications for channel function.

The voltage-gated sodium channel (VGNC) is targeted by naturally occurring ligands and drugs of diverse structure. ATP modulates VGNC current in-vitro but is given little prominence in models describing channel function. This computational study uses superimposition and molecular fitting to investigate relative molecular similarity within the structures of ATP and VGNC ligands. A motif of 3 linked atoms (C-N-C) in the adenine ring of ATP satisfies the fitting of a wide range of anticonvulsant structures. An alternative group (N-C-N) provides one fitting motif for the ester and amide groups of local anaesthetic drugs; protonated amine and aromatic groups in the same conformers fit to a second motif in the adenine ring. Analogous structures from other drug classes with VGNC blocking activity give the same molecular fits to ATP. Structures fitted to the adenine ring of ATP occlude the intra-molecular space between the nucleoside and triphosphate chain in approximation to their established blocking, activating or neutral effects on Na+ current. The findings are discussed in terms of drug preferences for VGNC states and channel requirements for ATP.

Hyperopia and educational attainment in a primary school cohort.

BACKGROUND: Vision screening addresses the visual impairments that impact on child development. Tests of long-sightedness are not found in most school screening programmes. The evidence linking mild-moderate hyperopia and lack of progress in school is insufficient, although strengthened by recent findings of developmental problems in infants. AIMS: To report on the relation between hyperopia and education test results in a cohort of primary school children. METHODS: A total of 1298 children, aged 8 years, were screened for hyperopia on the basis of fogging test results. School test results (NFER and SATs) were compared between groups categorised by referral status and refractive error. RESULTS: A total of 166 (12.8%) fogging test failures were referred for ophthalmic assessment. Ophthalmic tests on 105 children provided an accurate diagnosis of vision defects, for reference to their education scores. Fifty per cent of the children examined by optometrists required an intervention (prescription change, glasses prescribed, or referral). Mean (95% CI) NFER scores of children with refractive errors (summed for both eyes) >+3D (98.4, 93.0-103.8, n = 32) or >+1.25D (best eye) (99.3, 93.0-105.6, n = 26) were lower than the respective scores of children with a less positive refractive state (104.8, 100.7-108.9, n = 43) (103.6, 99.7-107.4, n = 49), the non-referred group, and total sample. The SATs results followed a similar trend. A high proportion of the fogging test failures (16%) and confirmed hyperopes (29%) had been referred to an educational psychologist, and the latter group contributed substantially to the poor education scores. CONCLUSIONS: The results of this study provide further evidence for a link between hyperopia and impaired literacy standards in children.

Receptor regulatory properties evident in the molecular similarity of serotonin receptor ligands and purine nucleotides.

Previous computational studies have explored the relative molecular similarity inherent in the ligands of neurotransmitter-regulated cell receptors and purine nucleotides. This study presents the results of an investigation of the major serotonin (5-HT) receptor classes, using molecular superimposition and fitting data. Ligands for 5HT(1B/C/D) and 5HT(4/7) receptors identified pharmacophores in the adenine ring of ATP. 5-HT(2) and 5-HT(3) receptor ligands identified pharmacophores in the guanosine nucleotide and cyclic nucleotide, respectively. The described molecular similarity is consistent with the cyclic nucleotide responses observed during signal transduction events initiated by 5-HT, and the reported similarity between ligands of the 5-HT(1B) and 5-HT(1D), 5-HT(1A) and 5-HT(7), and 5-HT(4) and 5-HT(3) receptors. The results are discussed in terms of current pharmacophoric models and signal transduction events involving interaction between G-protein receptors and catalytic sites.

Accidents in the school environment: perspectives of staff concerned with data collection and reporting procedures.

School-accident reports document incidents that have resulted in children requiring assistance from staff in the education and healthcare sectors. This study was undertaken to investigate the collection and use of data by agencies concerned with the school-accident problem. Our aim was to determine if the annual collection and use of such a large body of data might be improved through better management procedures. Interviews were conducted with primary and secondary school staff in one education authority. Interviewees completed a questionnaire on accident activity and accident reporting in their school. In the healthcare sector, staff from the Schools' Office and the ambulance unit servicing the schools provided information on their collection and use of data. Our survey found that accident activity is usually a private matter for individual schools, shared to varying degrees with the education authority. Playgrounds, children's behaviour and footwear carried much of the blame for the injuries sustained. Staff generally accepted the current accident rates. The compilation of accident data by the Schools' Office, accident and emergency department, and ambulance service were compromised by deficiencies in computerization and computer software. The management and utilization of school-accident data could be improved by better collaboration within and between the education and healthcare agencies.

Receptor regulatory properties evident in the molecular similarity of dopamine receptor ligands and purine nucleotides.

Computational studies have revealed similarities in the relative configurations of purine nucleotides and ligands for histamine, acetylcholine and adrenergic receptors. In common with other G-protein-regulated receptors, dopamine receptors are associated with specific changes in nucleotide levels during signal transduction processes. The purpose of this study was to investigate molecular similarity in dopamine receptor ligands and purine nucleotides. Molecular superimposition and fitting data for D1-like receptor ligands identified a pharmacophore in the adenine and ribose rings of ATP. D2-like agonists and antagonists related to a pharmacophore in the guanine and ribose rings of GTP. The results are consistent with the hypothesis that the dopamine receptor family may have evolved from receptors for the ATP and GTP nucleotides.

Secondary school accident reporting in one education authority.

BACKGROUND: Secondary schools appear to have very different accident rates when they are compared on the basis of accident report returns. The variation may be as a result of real differences in accident rates or different reporting procedures. This study investigates accident reporting from secondary schools and, in particular, the role of the school nurse. METHODS: Accident form returns covering a 2-year period were collected for statistical analysis from 13 comprehensive schools in one local education authority in Wales. School sites were visited in the following school year to obtain information about accident records held on site and accident reporting procedures. RESULTS: The main factors determining the number of school accident reports submitted to the education authority relate to differences in recording and reporting procedures, such as the employment of a nurse and the policy of the head teacher/safety officer on submitting accident returns. Accident and emergency department referrals from similar schools may show significant differences in specific injuries and their causes. CONCLUSIONS: The level of school accident activity cannot be gauged from reports submitted to the education authority. Lack of incentives for collecting good accident data, in conjunction with the degree of complacency in the current system, suggest that future accident rates and reporting activity are unlikely to change.

Primary school accident reporting in one education authority.

BACKGROUND: Studies have shown a correlation between increased accident rates and levels of deprivation in the community. School accident reporting is one area where an association might be expected. AIMS: To investigate differences in primary school accident rates in deprived and more affluent wards, in an area managed by one education authority. METHODS: Statistical analysis of accident form returns for 100 primary schools in one education authority in Wales over a two year period, in conjunction with visits to over one third of school sites. RESULTS: Accident report rates from schools in deprived wards were three times higher than those from schools in more affluent wards. School visits showed that this discrepancy was attributable primarily to differences in reporting procedures. One third of schools did not report accidents and approximately half did not keep records of minor accidents. CONCLUSIONS: The association between school accident report rates and deprivation in the community is complex. School accident data from local education authorities may be unreliable for most purposes of collection.

Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation.

We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.

Structure of outcome beliefs in condom use. The Project RESPECT Study Group.

To study the structure of beliefs about condom use outcomes, the authors derived and tested 4 psychosocial hypothetical models: (a) a 2-factor model of the personal and social outcomes of condom use; (b) a 2-factor model of the pros and cons of the behavior; (c) a 3-factor model (i.e., physical, self-evaluative, and social) of outcome expectancies; and (d) a thematic 4-factor model of the protection, self-concept, pleasure, and interaction implications of the behavior. All 4 models were studied with a confirmatory factor analysis approach in a multisite study of 4,638 participants, and the thematic solution was consistently the most plausible. Self-concept and pleasure were most strongly associated with attitudes toward using condoms, intentions to use condoms, and actual condom use, whereas protection and interaction generally had little influence.

Student nurse satisfaction: implications for the common foundation programme.

This decade has seen a major restructuring of pre-registration nurse education within the higher education system that was costly and initially largely unpopular with qualified nurses and students. Major flaws have been identified in the common foundation programme (CFP) and student attrition rates remain too high. Our detailed survey of student satisfaction within the CFP shows that clinical placement is the most popular course component and that poor organization remains the worst aspect of the course. Teaching was more highly regarded than the organizational component of the course, although students found room for improvement. Core teaching modules such as bioscience and nursing interventions achieved better ratings than supporting modules, for example social policy or research and reflection on practice. The establishment of contact between personal tutors and students appeared to be slow. The described deficiencies have since been addressed in curriculum planning and the development of new course structure.

Discontinuation, leaving reasons and course evaluation comments of students on the common foundation programme.

There is considerable financial incentive, at all levels, to reduce student nurse wastage and maintain recruitment to a workforce of professional nurses. This strategy is being pursued in a period following major educational change, when the attrition levels and leaving reasons of students need to be reassessed. Previous reports have identified a high voluntary loss of students on the common foundation programme (CFP) of the pre-registration nursing course. In order to achieve a better understanding of the basic problems faced by student nurses who consider leaving the CFP, questionnaires were distributed to three groups of students: current CFP students; students who had completed the CFP; and students who had discontinued training. The questionnaire responses show that course-based problems, identified as prime leaving reasons by the current and completed student groups, differ from the actual leaving reasons of discontinued students obtained by exit questionnaire. The attitudes of participating and discontinued students to theory, clinical and pastoral components of the CFP are not dissimilar. Some trends in attrition rate relate significantly to student category. Our results have implications for the management of student nurse attrition.

Chronic and recovered cases of sheep-associated malignant catarrhal fever in cattle.

Malignant catarrhal fever (MCF) is traditionally regarded as a disease with a short clinical course, low morbidity and high case fatality rate. Owing to the limitations of the assays used for laboratory diagnosis. It was difficult in characterise the clinical spectrum of sheep-associated MCF, particularly when the cattle recovered from an MCF-like clinical syndrome. Over a period of three years, 11 cattle that survived MCF for up to two-and-a-half years were identified on four premises. A clinical diagnosis of MCF was confirmed by the detection of ovine herpesvirus-2 DNA in peripheral blood leucocytes using a polymerase chain reaction (PCR) assay that detects a specific 238 base-pair fragment of viral genomic DNA. Of the 11 cattle examined, six recovered clinically with the exception of bilateral corneal oedema with stromal keratitis (four animals) and unilateral perforating keratitis (one animal). The 10 animals available for postmortem examination had disseminated subacute to chronic arteriopathy. Recovery was associated with the resolution of the acute lymphoid panarteritis that characterises the acute phase of MCF, and with the development of generalised chronic obliterative arteriosclerosis. Bilateral leucomata were due in part to the focal destruction of corneal endothelium secondary to acute endothelialitis. Formalin-fixed tissues and/or unfixed lymphoid cells from all 11 cattle were positive for sheep-associated MCF by PCR. These observations indicate that recovery and chronic disease are a significant part of the clinical spectrum of MCF and that such cases occur with some frequency in the area studied. The affected cattle remain persistently infected by the putative sheep-associated MCF gammaherpesvirus.

In vitro displacement of vasoactive mediators from plasma proteins: a possible mechanism for pseudo-allergic reactions to neuromuscular blocking drugs.

We have studied the release of prostaglandin F2 alpha (PGF2 alpha) and histamine from serum proteins by neuromuscular blocking drugs using equilibrium dialysis, with tracer quantities of radio-labelled mediators as probes. Small concentrations (0.05-0.25 mmol litre-1) of competitive neuromuscular blocking drugs displaced 16-67% of bound histamine. Greater concentrations of suxamethonium (2 mmol litre-1) were required for histamine displacement (19%). There was a significant release of PGF2 alpha by atracurium 1 mmol litre-1 and pancuronium 0.69 mmol litre-1. These findings suggest an alternative mechanism of histamine release by neuromuscular blocking drugs which may be relevant to adverse reactions during use.

Segregation analysis of cancer in families of childhood soft-tissue-sarcoma patients.

This paper presents the analysis of familial cancer data collected in a hospital-based study of 159 childhood soft-tissue-sarcoma patients. Two different statistical models detected excess aggregation of cancer, which could be explained by a rare dominant gene. For each kindred, we estimated the probability of the observed cancer distribution under the dominant-gene model and identified 12 families that are the most likely to be segregating the gene. Two of those families have confirmed germ-line mutations in the p53 tumor-suppressor gene. The relative risk of affection for children who are gene carriers was estimated to be 100 times the background rate. Females were found to have a slightly higher age-specific penetrance, but maternal and paternal lineages made equal contributions to the evidence in favor of the dominant gene. The proband's histology, ethnicity, and age at diagnosis were evaluated to determine whether any of these altered the probability of affection in family members. Only embryonal rhabdomyosarcoma was found to be a significant covariate under the dominant-gene model. While molecular genetic studies of familial cancer will eventually provide answers to the questions of genetic heterogeneity, age- and site-specific penetrance, mutation rates, and gene frequency, information from statistical models is useful for setting priorities and defining hypotheses.