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Since first described, acoels were considered members of the flatworms (Platyhelminthes). However, no clear synapomorphies among the three large flatworm taxa -- the Catenulida, the Acoelomorpha and the Rhabditophora -- have been characterized to date. Molecular phylogenies, on the other hand, commonly positioned acoels separate from other flatworms. Accordingly, our own multi-locus phylogenetic analysis using 43 genes and 23 animal species places the acoel flatworm Isodiametra pulchra at the base of all Bilateria, distant from other flatworms. By contrast, novel data on the distribution and proliferation of stem cells and the specific mode of epidermal replacement constitute a strong synapomorphy for the Acoela plus the major group of flatworms, the Rhabditophora. The expression of a piwi-like gene not only in gonadal, but also in adult somatic stem cells is another unique feature among bilaterians. These two independent stem-cell-related characters put the Acoela into the Platyhelminthes-Lophotrochozoa clade and account for the most parsimonious evolutionary explanation of epidermal cell renewal in the Bilateria. Most available multigene analyses produce conflicting results regarding the position of the acoels in the tree of life. Given these phylogenomic conflicts and the contradiction of developmental and morphological data with phylogenomic results, the monophyly of the phylum Platyhelminthes and the position of the Acoela remain unresolved. By these data, both the inclusion of Acoela within Platyhelminthes, and their separation from flatworms as basal bilaterians are well-supported alternatives.

Objective: To evaluate whether the adult smoking rate changed in Lexington-Fayette County, Kentucky, following the enactment of a smoke-free public places ordinance., Methods: Behavioral Risk Factor Surveillance System (BRFSS) data from 2001-2005 were used to test whether smoking rates changed in Fayette County from the pre- to post-law period, relative to the change in 30 Kentucky counties with similar demographics. The sample consisted of 10,413 BRFSS respondents: 7139 pre-law (40 months) and 3274 post-law (20 months)., Results: There was a 31.9% decline in adult smoking in Fayette County (25.7% pre-law to 17.5% post-law). In the group of 30 Control counties, the rate was 28.4% pre-law and 27.6% post-law. Controlling for seasonality, time trend, age, gender, ethnicity, education, marital status, and income, there was a significant Time (pre- vs. post-law) by Group (Fayette vs. Controls) interaction. There were an estimated 16,500 fewer smokers in Fayette County during post-law compared to pre-law., Conclusion: There was a significant effect of smoke-free legislation on adult smoking rates.

Background: The cichlid fishes in general, and the exceptionally diverse East African haplochromine cichlids in particular, are famous examples of adaptive radiation and explosive speciation. Here we report the collection and annotation of more than 12,000 expressed sequence tags (ESTs) generated from three different cDNA libraries obtained from the East African haplochromine cichlid species Astatotilapia burtoni and Metriaclima zebra., Results: We first annotated more than 12,000 newly generated cichlid ESTs using the Gene Ontology classification system. For evolutionary analyses, we combined these ESTs with all available sequence data for haplochromine cichlids, which resulted in a total of more than 45,000 ESTs. The ESTs represent a broad range of molecular functions and biological processes. We compared the haplochromine ESTs to sequence data from those available for other fish model systems such as pufferfish (Takifugu rubripes and Tetraodon nigroviridis), trout, and zebrafish. We characterized genes that show a faster or slower rate of base substitutions in haplochromine cichlids compared to other fish species, as this is indicative of a relaxed or reinforced selection regime. Four of these genes showed the signature of positive selection as revealed by calculating Ka/Ks ratios., Conclusion: About 22% of the surveyed ESTs were found to have cichlid specific rate differences suggesting that these genes might play a role in lineage specific characteristics of cichlids. We also conclude that the four genes with a Ka/Ks ratio greater than one appear as good candidate genes for further work on the genetic basis of evolutionary success of haplochromine cichlid fishes.

Purpose: Adequate caloric intake is associated with improved outcome in neurocritical illness, but factors influencing the provision of enteral nutrition (EN) have not been systematically evaluated. The primary goal of the study was to determine the EN intake of neurosurgical intensive care unit (ICU) patients within the first week of illness and investigate the factors contributing to achieving caloric goals., Methods: A retrospective cohort of adult patients admitted to the neurosurgery service (NS) during August 2005-August 2006 were randomly selected and stratified into three groups based on their ICU-admission Glasgow Coma Scale Score (GCS) (GCS > 11, GCS 8-11, GCS 4-7). Daily EN intake, GCS, and other clinical data were collected., Results: A total of 71 patients were included (GCS > 11 = 23, GCS 8-11 = 23, GCS 4-7 = 25). Admitting diagnoses included traumatic brain injury (TBI) (32%), subarachnoid hemorrhage (SAH) (32%), and intracerebral hemorrhage (17%). The overall in-hospital mortality was 23.9%. Overall, the maximum daily mean calories provided was 1,100 kcal (mean of 55% of caloric goal on hospital day 6). The median time to feeding was approximately 3 days in each group. GCS did not appear to significantly affect the mean % of caloric goal administered in patients with a minimum daily GCS < or = 11 (P = 0.053). Multivariate analysis revealed that clinical care factors, such as time to EN orders and enteral access confirmation, were significant impediments to EN provision (P = 0.001)., Conclusion: System-based clinical care factors appear to have great impact on the successful provision of EN in the first week of neurocritical illness.

Biodiversity studies require species level analyses for the accurate assessment of community structures. However, while specialized taxonomic knowledge is only rarely available for routine identifications, DNA taxonomy and DNA barcoding could provide the taxonomic basis for ecological inferences. In this study, we assessed the community structure of sediment dwelling, morphologically cryptic Chironomus larvae in the Rhine-valley plain/Germany, comparing larval type classification, cytotaxonomy, DNA taxonomy and barcoding. While larval type classification performed poorly, cytotaxonomy and DNA-based methods yielded comparable results: detrended correspondence analysis and permutation analyses indicated that the assemblages are not randomly but competitively structured. However, DNA taxonomy identified an additional species that could not be resolved by the traditional method. We argue that DNA-based identification methods such as DNA barcoding can be a valuable tool to increase accuracy, objectivity and comparability of the taxonomic assessment in biodiversity and community ecology studies.

Background: Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs., Methods/design: A population-based retrospective cohort study will follow up all those who have had an incident liver function test (LFT) in primary care to subsequent liver disease or mortality over a period of 15 years (approx. 2.3 million tests in 99,000 people). The study is set in Primary Care in the region of Tayside, Scotland (pop approx. 429,000) between 1989 and 2003. The target population consists of patients with no recorded clinical signs or symptoms of liver disease and registered with a GP. The health technologies being assessed are LFTs, viral and auto-antibody tests, ultrasound, CT, MRI and liver biopsy. The study will utilise the Epidemiology of Liver Disease In Tayside (ELDIT) database to determine the outcomes of liver disease. These are based on hospital admission data (Scottish Morbidity Record 1), dispensed medication records, death certificates, and examination of medical records from Tayside hospitals. A sample of patients (n = 150) with recent initial ALF tests or invitation to biopsy will complete questionnaires to obtain quality of life data and anxiety measures. Cost-effectiveness and cost utility Markov model analyses will be performed from health service and patient perspectives using standard NHS costs. The findings will also be used to develop a computerised clinical decision support tool., Discussion: The results of this study will be widely disseminated to primary care, as well as G.I. hospital specialists through publications and presentations at local and national meetings and the project website. This will facilitate optimal decision-making both for the benefit of the patient and the National Health Service.

Introduction: Adverse drug reaction (ADR) reporting makes a vital contribution to pharmacovigilance, although the factors that influence the reporting rate remain unclear. The aim of this study was to investigate whether the variation in the rate of reporting of suspected ADRs in different regions of Scotland was explained by differences in local prescribing practice and to quantify the extent of this influence., Methods: Population and primary care prescribing data were obtained for ten geographical areas based on the 15 administrative regions of the National Health Service in Scotland. All reports of suspected ADRs received from within Scotland for 2000 and 2001 were available from the regional monitoring centre (Committee on Safety of Medicines, Scotland). The primary analysis was based on 14 medications that appeared in the 'top ten' list for the frequency of reported ADRs for either year. Reporting rates for each area were expressed both in terms of population (reports per million people) and in terms of estimated exposure to those medications in primary care (reports per 1000 prescriptions). For each analysis, the Pearson correlation coefficient between reporting and prescribing data was calculated using SPSS software., Results: The 'top ten' medications accounted for 1715 of 2817 (60.9%, 95% CI 59.1, 62.7) ADR reports but only 2.2 million out of a total of 128 million primary care prescriptions (1.7%). Although there was a 3-fold geographical variation in the per-population ADR reporting rate, there was a close correlation between local reporting of ADRs and prescribing of the index medications (p = 0.66, p = 0.04, respectively). This implies that 44% of the observed variation in reporting rate can be attributed to variation in prescribing within the same population., Discussion: Spontaneous ADR reporting in Scotland over the 2 years studied was highly concentrated on a small number of medications that were under intensive surveillance. Although there was a 3-fold variation in reporting rates from individual geographic areas when corrected for the size of the population, primary care prescribing data showed nearly half of this local variation in reporting rates could be explained by differences in prescribing. This study highlights the importance of considering prescribing practice when interpreting spontaneous ADR reporting data.

Background: Evolution of the deuterostome lineage was accompanied by an increase in systematic complexity especially with regard to highly specialized tissues and organs. Based on the observation of an increased number of paralogous genes in vertebrates compared with invertebrates, two entire genome duplications (2R) were proposed during the early evolution of vertebrates. Most glycolytic enzymes occur as several copies in vertebrate genomes, which are specifically expressed in certain tissues. Therefore, the glycolytic pathway is particularly suitable for testing theories of the involvement of gene/genome duplications in enzyme evolution., Results: We assembled datasets from genomic databases of at least nine vertebrate species and at least three outgroups (one deuterostome and two protostomes), and used maximum likelihood and Bayesian methods to construct phylogenies of the 10 enzymes of the glycolytic pathway. Through this approach, we intended to gain insights into the vertebrate specific evolution of enzymes of the glycolytic pathway. Many of the obtained gene trees generally reflect the history of two rounds of duplication during vertebrate evolution, and were in agreement with the hypothesis of an additional duplication event within the lineage of teleost fish. The retention of paralogs differed greatly between genes, and no direct link to the multimeric structure of the active enzyme was found., Conclusion: The glycolytic pathway has subsequently evolved by gene duplication and divergence of each constituent enzyme with taxon-specific individual gene losses or lineage-specific duplications. The tissue-specific expression might have led to an increased retention for some genes since paralogs can subdivide the ancestral expression domain or find new functions, which are not necessarily related to the original function.

The power of comparative phylogenomic analyses also depends on the amount of data that are included in such studies. We used expressed sequence tags (ESTs) from fish model species as a proof of principle approach in order to test the reliability of using ESTs for phylogenetic inference. As expected, the robustness increases with the amount of sequences. Although some progress has been made in the elucidation of the phylogeny of teleosts, relationships among the main lineages of the derived fish (Euteleostei) remain poorly defined and are still debated. We performed a phylogenomic analysis of a set of 42 of orthologous genes from 10 available fish model systems from seven different orders (Salmoniformes, Siluriformes, Cypriniformes, Tetraodontiformes, Cyprinodontiformes, Beloniformes, and Perciformes) of euteleostean fish to estimate divergence times and evolutionary relationships among those lineages. All 10 fish species serve as models for developmental, aquaculture, genomic, and comparative genetic studies. The phylogenetic signal and the strength of the contribution of each of the 42 orthologous genes were estimated with randomly chosen data subsets. Our study revealed a molecular phylogeny of higher-level relationships of derived teleosts, which indicates that the use of multiple genes produces robust phylogenies, a finding that is expected to apply to other phylogenetic issues among distantly related taxa. Our phylogenomic analyses confirm that the euteleostean superorders Ostariophysi and Acanthopterygii are monophyletic and the Protacanthopterygii and Ostariophysi are sister clades. In addition, and contrary to the traditional phylogenetic hypothesis, our analyses determine that killifish (Cyprinodontiformes), medaka (Beloniformes), and cichlids (Perciformes) appear to be more closely related to each other than either of them is to pufferfish (Tetraodontiformes). All 10 lineages split before or during the fragmentation of the supercontinent Pangea in the Jurassic.

Background: Gene and genome duplication events increase the amount of genetic material that might then contribute to an increase in the genomic and phenotypic complexity of organisms during evolution. Thus, it has been argued that there is a relationship between gene copy number and morphological complexity and/or species diversity. This hypothesis implies that duplicated genes have subdivided or evolved novel functions compared to their pre-duplication proto-orthologs. Such a functional divergence might be caused by an increase in evolutionary rates in one ortholog, by changes in expression, regulatory evolution, insertion of repetitive elements, or due to positive Darwinian selection in one copy. We studied a set of 2466 genes that were present in Danio rerio, Takifugu rubripes, Tetraodon nigroviridis and Oryzias latipes to test (i) for forces of positive Darwinian selection; (ii) how frequently duplicated genes are retained, and (iii) whether novel gene functions might have evolved., Results: 25% (610) of all investigated genes show significantly smaller or higher genetic distances in the genomes of particular fish species compared to their human ortholog than their orthologs in other fish according to relative rate tests. We identified 49 new paralogous pairs of duplicated genes in fish, in which one of the paralogs is under positive Darwinian selection and shows a significantly higher rate of molecular evolution in one of the four fish species, whereas the other copy apparently did not undergo adaptive changes since it retained the original rate of evolution. Among the genes under positive Darwinian selection, we found a surprisingly high number of ATP binding proteins and transcription factors., Conclusion: The significant rate difference suggests that the function of these rate-changed genes might be essential for the respective fish species. We demonstrate that the measurement of positive selection is a powerful tool to identify divergence rates of duplicated genes and that this method has the capacity to identify potentially interesting candidates for adaptive gene evolution.

Background: Costly structures need to represent an adaptive advantage in order to be maintained over evolutionary times. Contrary to many other conspicuous shell ornamentations of gastropods, the haired shells of several Stylommatophoran land snails still lack a convincing adaptive explanation. In the present study, we analysed the correlation between the presence/absence of hairs and habitat conditions in the genus Trochulus in a Bayesian framework of character evolution., Results: Haired shells appeared to be the ancestral character state, a feature most probably lost three times independently. These losses were correlated with a shift from humid to dry habitats, indicating an adaptive function of hairs in moist environments. It had been previously hypothesised that these costly protein structures of the outer shell layer facilitate the locomotion in moist habitats. Our experiments, on the contrary, showed an increased adherence of haired shells to wet surfaces., Conclusion: We propose the hypothesis that the possession of hairs facilitates the adherence of the snails to their herbaceous food plants during foraging when humidity levels are high. The absence of hairs in some Trochulus species could thus be explained as a loss of the potential adaptive function linked to habitat shifts.

DNA barcoding is a promising approach to the diagnosis of biological diversity in which DNA sequences serve as the primary key for information retrieval. Most existing software for evolutionary analysis of DNA sequences was designed for phylogenetic analyses and, hence, those algorithms do not offer appropriate solutions for the rapid, but precise analyses needed for DNA barcoding, and are also unable to process the often large comparative datasets. We developed a flexible software tool for DNA taxonomy, named TaxI. This program calculates sequence divergences between a query sequence (taxon to be barcoded) and each sequence of a dataset of reference sequences defined by the user. Because the analysis is based on separate pairwise alignments this software is also able to work with sequences characterized by multiple insertions and deletions that are difficult to align in large sequence sets (i.e. thousands of sequences) by multiple alignment algorithms because of computational restrictions. Here, we demonstrate the utility of this approach with two datasets of fish larvae and juveniles from Lake Constance and juvenile land snails under different models of sequence evolution. Sets of ribosomal 16S rRNA sequences, characterized by multiple indels, performed as good as or better than cox1 sequence sets in assigning sequences to species, demonstrating the suitability of rRNA genes for DNA barcoding.

In this study, we present a molecular phylogeny for the west Palaearctic Helicidae sensu lato based on sequence data from two mitochondrial (COI, 16S rDNA) and two nuclear (ITS-1, 18S rDNA) genes. Maximum likelihood analysis and Bayesian inference revealed well supported monophyletic clades partly conflicting traditional classifications. Based on these results, we propose the following system. The Western Palaearctic Helicidae s.l. consist of two families, Helicidae and Hygromiidae. Within the Helicidae, three well supported subfamilies can be recognised: the Helicinae, Ariantinae, and Helicodontinae. The Hygromiidae consist of three clades: the Hygromiinae, the Helicellinae, and a yet unnamed clade comprising the genera Sphincterochila and Cochlicella. We then used the phylogeny to study the evolution of anatomical, and ecological characters traditionally used for systematic classification. In the Helicidae s.l., two independent evolutionary transitions to life in xeric environments occurred, which allowed the occupation of new niches with a subsequent radiation of the Helicellinae-Cochlicella/Sphincterochila clade and the Helicinae. Whereas, the multiplication of the Glandulae mucosae is a synapomorphy of the Hygromiidae, the lovedart sac apparatus is present in all groups and thus, the trait cannot provide a synapomorphy for either families or subfamilies. Additionally, we evaluated the use of structural molecular genetic characters for taxonomic assessment. The presence of an unique loop region of the 16S rDNA gene and a short tandem repeat in the ITS-1 region provide independent evidence for the monophyly of these major two groups, and can be used for preliminary classification.

Objective: To look for evidence of a relation between antibiotic resistance and prescribing by general practitioners by analysis of prescribing at both practice and individual patient level., Design: Repeated cross-sectional study in 1995 and 1996., Setting: 28 general practices in the Ninewells Hospital laboratory catchment area, Tayside, Scotland. SUBJECTS REVIEWED: 8833 patients registered with the 28 practices who submitted urine samples for analysis., Main Outcome Measures: Resistance to trimethoprim in bacteria isolated from urine samples at practice and individual level simultaneously in a multilevel model., Results: Practices showed considerable variation in both the prevalence of trimethoprim resistance (26-50% of bacteria isolated) and trimethoprim prescribing (67-357 prescriptions per 100 practice patients). Although variation in prescribing showed no association with resistance at the practice level after adjustment for other factors (P = 0.101), in the multilevel model resistance to trimethoprim was significantly associated with age, sex, and individual-level exposure to trimethoprim (P < 0.001) or to other antibiotics (P = 0.002). The association with trimethoprim resistance was strongest for people recently exposed to trimethoprim, and there was no association for people with trimethoprim exposure more than six months before the date of the urine sample., Discussion: Analysis of practice level data obscured important associations between antibiotic prescribing and resistance. The results support efforts to reduce unnecessary prescribing of antibiotics in the community and show the added value of individual patient data for research on the outcomes of prescribing.

The reported association between antibiotic prescribing and resistance may be subject to bias or confounding. Bias describes any effect at any stage of investigation or inference tending to produce results that depart systematically from the true value. A confounding variable is one that is associated independently with both exposure and outcome. Confounding variables may create an apparent association or mask a real association. Pharmacoepidemiology is the study of the use and the effects of drugs in large numbers of people. We have used standard pharmacoepidemiological methods to investigate sources of bias and confounding in the association between prescribing and resistance. We conclude that the association is statistically valid and that the consistency of evidence supports a cause-effect relationship. Nonetheless, several important sources of bias and confounding must be taken into account in future studies that analyze the impact of prescribing policies on resistance.

In order to detect adverse drug reactions, large observational drug safety studies are necessary as randomized clinical trials rarely have enough power. However, in order to obtain reliable results the issue of confounding, especially confounding by indication, should be addressed. We proposed a multiple propensity score, which is an extension of the propensity score, to reduce the bias in a dose-response analysis in a drug safety study. The multiple propensity score has similar properties to the propensity score in Rosenbaum and Rubin.(1) Using the propensity score for bias reduction of the risk ratio was considered. We used the multiple propensity score in a study of the dose-response relationship between diclofenac prescriptions and hospitalization for gastrointestinal bleeding and perforation using a record linkage database. We found that the unadjusted risk ratios were biased downwards due to confounders and that this bias was reduced by using stratification based on the multiple propensity score.

Objective: To estimate mortality by drug use in a cohort of patients with PD relative to age- and sex-matched comparators., Methods: two longitudinal cohorts of patients with 7 and 11 years' duration of PD were constructed with matched comparators in Tayside, Scotland. Subjects were eligible for inclusion if they received a first prescription for an anti-Parkinson's drug from July 1989 to December 1995, with no PD drug prescription in the previous 6 months. Those who had previously taken a neuroleptic drug or were younger than 40 years of age were excluded., Results: Overall, subjects with PD in relation to comparators had higher mortality with a rate ratio (RR) of 1.76 (95% CI 1.11, 2.81) in the 7-year cohort. There was significantly greater mortality in patients with PD who received levodopa monotherapy (RR = 2.45, 95% CI 1.42, 4.23) relative to the comparators, adjusting for previous cardiovascular drug use and diabetes. However, there was no significant difference in mortality in those with PD receiving combination therapy of selegiline with levodopa and other drugs in relation to the comparators (RR = 0.92, 95% CI 0.37, 2.31)., Conclusions: Subjects with PD had twice the rate of mortality relative to age- and sex-matched comparators. However, those subjects who received selegiline at any time in combination with co-careldopa or co-beneldopa showed no significant difference in mortality compared with the comparators. Monotherapy with levodopa was associated with the highest mortality.

The authors present a case of heparin-induced thrombocytopenia and thrombosis (HITT) that occurred after aneurysmal subarachnoid hemorrhage (SAH), and they review the relevant literature. An immune-mediated syndrome, HITT is characterized by moderate thrombocytopenia and paradoxical vascular thromboses. Although it has been estimated in prospective studies that HITT occurs in between 1 and 3% of patients receiving heparin, it is underrecognized in the neurosurgical literature. In the present case, a 49-year-old woman underwent clipping of a right posterior communicating artery aneurysm after suffering a Hunt and Hess Grade III SAH. She had an uncomplicated postoperative course with good clip positioning and no vasospasm observed on a cerebral angiogram obtained on Day 7. On Day 23, the patient developed a right hemiparesis and experienced a grand mal seizure. A head computerized tomography scan revealed a hemorrhagic infarct in the left middle cerebral artery distribution. Repeated cerebral angiograms did not show vasospasm. She was thrombocytopenic (platelet count as low as 46 x 10(9)/L on Day 28 compared with 213 x 10(9)/L on Day 1) and had been receiving heparin flushes to maintain intravenous catheter patency. An assay for HITT-associated antibodies was positive. The heparin flushes were discontinued and the platelet count recovered (121 x 10(9)/L). She improved neurologically, but was left with a significant right hemiparesis at discharge. This patient had assay-proven heparin-induced thrombocytopenia despite minimal exposure to heparin. Because there was no evidence of vasospasm or other factors to account for her delayed hemorrhagic infarction, an HITT-related disorder seemed most likely. Despite a large body of literature describing HITT in nonneurosurgical patients, only three previous neurosurgical cases have been published. This case report may serve to heighten awareness of this disorder.

Background and Purpose: Digital subtraction angiography (DSA) is the standard of reference for detecting cerebral vasospasm after subarachnoid hemorrhage (SAH). CT angiography (CTA) is a relatively recent method for depicting the intracranial arterial vasculature. The purpose of this study was to compare CTA and DSA in the detection and quantification of cerebral vasospasm., Methods: Seventeen patients with SAH underwent initial CTA with or without DSA and follow-up CTA and DSA. The follow-up CTA and DSA studies were performed within 24 hours of each other and 5 to 10 days after SAH. Maximum intensity projection images were produced for each CTA. Six arterial locations were examined for spasm: the suprasellar internal carotid artery (ICA), the M1 and M2 segments of the middle cerebral artery, the A1 and A2 segments of the anterior cerebral artery, and the basilar artery. Vasospasm was categorized as none, mild (<30% luminal reduction), moderate (30% to 50% reduction), or severe (>50% reduction)., Results: The overall correlation between CTA and DSA was 0.757, but was better for proximal than distal locations (0.88-1.00 versus 0.152-0.446). Agreement between CTA and DSA was greater for no spasm (92%) and severe spasm (100%) than for mild (57%) or moderate (64%) spasm. CTA was highly accurate for no spasm or severe spasm in proximal locations (96%, and 100%, respectively); it was less accurate (90% and 95%, respectively) for mild or moderate spasm in these locations. For distal locations, the accuracy for absent, mild, moderate, or severe spasm was 78%, 81%, 94%, and 100%, respectively., Conclusion: CTA is highly sensitive, specific, and accurate in detecting no spasm or severe cerebral vasospasm in proximal arterial locations; it is less accurate for detecting mild and moderate spasm in distal locations.

Trimethoprim is a safe, effective, and inexpensive treatment for cystitis. However, at least 25% of bacteria isolated from urine samples in general practice are now resistant to trimethoprim in the laboratory. The relationship between laboratory resistance and clinical outcome is complex. Cephalexin appears to be more active than trimethoprim in the laboratory but has been consistently less effective in clinical trials. There is little point in collecting data about the prevalence of drug resistance in urinary bacteria unless it is linked to evidence about the impact of resistance on clinical outcomes. Pragmatic clinical trials are required to provide practices with clear thresholds for managing their antibiotic policies; for example, 'Change from trimethoprim to drug X when the probability of trimethoprim resistance reaches Y%.' Prescribers should be aware that trimethoprim resistance is most likely to occur in patients who have been exposed to trimethoprim or other antibiotics in the previous six months, and that the risk increases with age. This information could be used to stratify women according to risk of infection by trimethoprim-resistant bacteria. Health education leaflets are an effective method for reducing the frequency of recurrent cystitis. Symptomatic treatment can control symptoms and allow time for microbiological investigation. Both of these strategies may help to reduce unnecessary prescribing of antibiotics in general and quinolones in particular.

Objective: Computed tomographic angiography (CTA) is a rapid and minimally invasive method of detecting intracranial aneurysms. We wished to determine whether CTA could replace digital subtraction angiography (DSA) in the diagnosis and operative planning of ruptured cerebral aneurysms., Methods: In a prospective study, patients with subarachnoid hemorrhage diagnosed by plain computed tomography underwent CTA, DSA, or both. Computed tomographic scans and CTA studies were first reviewed by the treating surgeon, along with a neuroradiologist, and a decision to proceed to DSA or directly to surgery was made on the basis of the type and quality of information provided by CTA. All patients underwent postoperative DSA., Results: A total of 173 patients were studied. In 24 patients, both CTA and DSA were negative for a source of subarachnoid hemorrhage. Twelve patients underwent DSA without prior CTA because a technologist capable of performing CTA was not available when the patient was evaluated. Nine patients in poor neurological condition underwent CTA, and all tested positive for aneurysms but died without surgical intervention. Of the 126 patients who underwent CTA and surgery, 65 (52%) also required preoperative DSA. The decision to proceed to DSA after CTA was influenced by aneurysm location; posterior communicating artery (62%) and posterior circulation locations (67-75%) more commonly proceeded to DSA than middle cerebral artery aneurysms (34%; 0.025 > P > 0.01). The sensitivity and specificity of CTA for the detection of all aneurysms, ruptured and unruptured, in the group of patients who underwent both types of angiograms preoperatively were 84 and 100%, respectively. In the group of 61 patients in whom aneurysm surgery was performed on the basis of CTA results alone, the sensitivity and specificity for the detection of all aneurysms, as compared with postoperative DSA, were 90 and 100%, respectively. Missed aneurysms (n = 24) were always small (<4 mm) and were usually found in patients with multiple aneurysms in whom the larger, ruptured aneurysm was identified by CTA. In one patient, the aneurysm missed by preoperative CTA would have resulted in a different operation if detected preoperatively., Conclusion: It is possible to proceed to ruptured aneurysm repair entirely on the basis of good-quality CTA studies that demonstrate an aneurysm consistent with the pattern of bleeding observed on plain computed tomography (48% of the patients in this series and most common middle cerebral artery aneurysms). However, detection of small unruptured aneurysms in patients with multiple lesions remains a problem.

The doctor-patient relationship has been described in economic terms as an 'agency relationship' where informed agents make decisions for uninformed clients. However, the decision to prescribe and the decision to accept the prescription by the patient are more complex in nature and involve many variables. Other factors, such as the 'need' for the prescription and the disease state (acute or chronic) also influence prescribing practice. Communication between the physician and patient was found to be important for rational and effective prescribing. The client can make better decisions with the relevant information, thus breaking down the agency relationship that once existed.

The aim of this study was to investigate the association between H(2)-receptor antagonists and acute pancreatitis. The automated database of the Medicines Monitoring Unit (MEMO) was used to carry out a case-control study, supplemented with information on possible confounding factors from hospital and GP medical records. Cases were patients hospitalized with a computerized diagnosis of acute pancreatitis, and two sets of controls were drawn from (1) the study population and from (2) the same GP practice as the case. Current or 60-day exposure to cimetidine and ranitidine was analysed. In adjusted analyses, cimetidine exposure and ranitidine exposure were associated with an increased risk of hospitalization for acute pancreatitis, as were alcohol abuse and cholelithiasis. The risks were lower in unadjusted analyses, suggesting that the association is confounded, although they did not disappear completely. A possible explanation is that data on confounding were incomplete. This study cannot discount the existence of an association between H(2)-antagonists and acute pancreatitis, and highlights the difficulties involved in obtaining complete and accurate data on confounding factors that are not collected routinely., (Copyright 1998 John Wiley & Sons, Ltd.)

Objective: To objectively compare computed tomographic angiography (CTA) with selective digital subtraction angiography (DSA) in the detection and anatomic definition of intracranial aneurysms, particularly in the setting of acute subarachnoid hemorrhage (SAH)., Methods: In a blinded prospective study, 40 patients with known or suspected intracranial saccular aneurysms underwent both CTA and DSA, including 32 consecutive patients with SAH in whom CTA was performed after CT images were obtained diagnostic for SAH. The CT angiograms were interpreted for presence, location, and size of the aneurysms, and anatomic features, such as the number of aneurysms lobes, aneurysm neck size (< or = 4 mm), and the number of adjacent arterial branches were suggested. The images obtained with CTA were then compared with the images obtained with DSA, with the later images serving as controls., Results: DSA revealed 43 aneurysms in 30 patients and ruled out intracranial aneurysms in the remaining 10 patients. For aneurysm presence alone, the sensitivity and specificity for CTA was 86 and 90%, respectively. For the presence of an aneurysms, six CT angiogram showed false negative results and one CT angiogram showed a false positive result. False negative results were usually caused by technical problems with the image, tiny aneurysm domes (< 3 mm), and unusual aneurysm locations (i.e., intracavernous carotid or posterior inferior cerebellar artery aneurysms). The results obtained with CTA were, compared with the results obtained with DSA, more than 95% accurate in determining dome and neck size of aneurysm, aneurysm lobularity, and the presence and number of adjacent arterial branches. In addition, CTA provided a three-dimensional representation of the aneurysmal lesion, which was considered useful for surgical planning., Conclusion: CTA is useful for rapid and relatively noninvasive detection of aneurysms in common locations, and the anatomic information provided in images showing positive results is at least equivalent to that provided by DSA. In cases of SAH in which the nonaugmented CT and CTA results indicate a clear source of bleeding and provide adequate anatomic detail, we think it is possible to forego DSA before urgent early aneurysm surgery. In all other cases, DSA is indicated.

Due to the broad substrate spectrum and stability in some water-miscible organic solvents, the peptide amidase from orange flavedo was found to be a suitable enzyme for experiments in water-miscible organic solvents. Immobilization and the kind of organic solvent had no significant influence on the kinetic data while the polarity of the substrate caused a great difference in the apparent Km values. The results are explained by inadequate partition of the substrate between the microenvironment of the enzyme and the reaction solution.

Enzyme-catalyzed peptide bond formation requires thorough examination and optimization of each coupling step. In order to identify factors influencing the selectivity between aminolysis and hydrolysis, a systematic study was carried out for the kinetically controlled peptide synthesis. The reaction temperature, the type of C-terminal protecting group, and different organic cosolvents showed little influence on the selectivity. The enzyme, excess nucleophile, pH, N-terminal protecting group, and ionic strength of the solution were identified as major factors controlling the selectivity and, therefore, the yield of the dipeptide synthesis. Under optimized conditions, the selectivity of the chymotrypsin-catalyzed synthesis of PheSer could be increased from 35 to 100%.

Ninety-four patients with hydrocephalus following subarachnoid haemorrhage were investigated. Fourteen of these patients had temporary ventricular drains inserted, 19 had drains that were later converted to ventricular-peritoneal shunts, and 61 patients had shunts only. All patients were analysed with respect to their grade on admission, the distribution of blood on CT scan, their Glasgow Coma Score, their intracranial pressure, and the presence or absence of vasospasm on angiography. Outcome was analysed by shunt procedure and time of shunt insertion. The higher the grade on admission, the more likely it was the patient would require a shunt. Fewer patients with a good outcome required shunting as compared to those whose outcome was poor. Patients having more subarachnoid blood on CT scan tended to present with a lower Glasgow Coma Score. The outcome of patients with intraventricular haemorrhage was not obviously influenced by the insertion of a ventriculostomy. Vasospasm was not more common in patients requiring a ventriculo-peritoneal shunt, nor did early shunting in patients with hydrocephalus affect the incidence of vasospasm. The majority of patients were either shunted in the first three days or after 30 days post-SAH. The outcome was better in those patients shunted at a later date.

The efficacy of U74006F in the prophylaxis of chronic cerebral vasospasm (VSP) was evaluated in a randomized, double-blind, placebo-controlled trial. Forty cynomolgus monkeys were divided by restricted randomization into 2 treatment groups of 20. Five animals from each treatment group were randomized into subgroups 1 and 2. The animals of subgroup 1 were studied pathologically. Brain biopsies of the animals in subgroup 2 were performed and studied with high-performance liquid chromatography (HPLC). The remaining 20 animals supplemented the number studied angiographically. Significant VSP (P less than 0.05) was detected in the majority of vessels from the clot site (right) of both treatment groups. Electron microscopy results showed positive correlation with the angiographic data. When comparing the effects of U74006F to those of the placebo at day 7, there was a significant difference (P less than 0.05) in the degree of VSP in the right extradural internal carotid and right middle cerebral arteries. This resulted from a greater degree of VSP in placebo animals. Two animals developed delayed ischemic deficits, one from each group. The infarct of the U74006F animal was smaller than the infarct in the placebo animal. Although overall changes in phosphagen levels did not reach statistical significance, HPLC analysis of the cortical biopsies did show a decrease in the ATP/ADP +/- AMP ratio of 54% in placebo animals and only 7% in animals receiving U74006F. The middle cerebral arteries of 2 animals were also studied with HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and efficacy of the thrombolytic agent tissue-type plasminogen activator (tPA) in the elimination of subarachnoid clot and prevention of chronic vasospasm were evaluated in a blind randomized placebo-controlled trial. Twenty-four monkeys were randomly assigned to one of two groups of 12. Each group underwent baseline cerebral angiography and coagulation analysis followed by right-sided craniectomy and experimental subarachnoid hemorrhage (SAH). An Ommaya reservoir was inserted with its catheter placed into the subarachnoid space. Twenty-four hours later one group (the tPA group) received 0.5 mg of tPA in 0.5 ml of buffer injected into the reservoir every 8 hours for three doses, while the second group (the placebo group) received the same volume of normal saline. On Day 7, angiography was repeated and the animals were sacrificed. One animal from the placebo group developed a delayed ischemic neurological deficit on Day 5 after SAH. Moderate to severe vasospasm (greater than 30% reduction in vessel caliber) was present on Day 7 in the internal carotid and middle cerebral arteries of the animals in the placebo group (p less than 0.01), while in the tPA group only mild narrowing of the anterior cerebral artery was seen. No significant change in coagulation status occurred in either group. All animals in the placebo group had a large amount of subarachnoid clot remaining at the time of sacrifice, but 11 of the 12 animals in the tPA group were completely free of clot. The results of electron microscopic studies of the cerebral arteries correlated with angiography, and there was no histological evidence of brain inflammation associated with the intrathecal use of tPA.