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PubMed2004

Large-scale identification of genes required for full virulence of Staphylococcus aureus.

Gene products required for in vivo growth and survival of microbial pathogens comprise a unique functional class and may represent new targets for antimicrobial chemotherapy, vaccine construction, or diagnostics. Although some factors governing Staphylococcus aureus pathogenicity have been identified and studied, a comprehensive genomic analysis of virulence functions will be a prerequisite for developing a global understanding of interactions between this pathogen and its human host. In this study, we describe a genetic screening strategy and demonstrate its use in screening a collection of 6,300 S. aureus insertion mutants for virulence attenuation in a murine model of systemic infection. Ninety-five attenuated mutants were identified, reassembled into new pools, and rescreened using the same murine model. This effort identified 24 highly attenuated mutants, each of which was further characterized for virulence attenuation in vivo and for growth phenotypes in vitro. Mutants were recovered in numbers up to 1,200-fold less than wild type in the spleens of systemically infected animals and up to 4,000-fold less than wild type in localized abscess infections. Genetic analysis of the mutants identified insertions in 23 unique genes. The largest gene classes represented by these mutants encoded enzymes involved in small-molecule biosynthesis and cell surface transmembrane proteins involved in small-molecule binding and transport. Additionally, three insertions defined two histidine kinase sensor-response regulator gene pairs important for S. aureus in vivo survival. Our findings extend the understanding of pathogenic mechanisms employed by S. aureus to ensure its successful growth and survival in vivo. Many of the gene products we have identified represent attractive new targets for antibacterial chemotherapy.

Animals↗
PubMed2001

New approaches to the understanding of the molecular basis of oral cancer.

Cancers of the oral cavity, salivary glands, larynx, and pharynx, collectively referred to as squamous cell carcinomas of the head and neck (HNSCC), are the sixth most common cancer among men in the developed world. The prognosis of HNSCC patients is still poor, which reflects the fact that although the risk factors for HNSCC are well-recognized, very little is known about the molecular mechanisms responsible for this malignancy. This review describes some of the current efforts and technological advances that have focused on the creation of a complete information infrastructure for genes expressed during squamous cell carcinogenesis. These include: the recently described HNSCC-specific chromosomal alterations (cCAP); the Head and Neck Cancer Genome Anatomy Project (HN-CGAP), whose goal is the systematic identification and cataloguing of known and novel genes expressed during tumor development; and the use of laser-capture microdissection (LCM), which is pivotal for the comprehensive molecular characterization of normal, pre-cancerous, and malignant cells by means of DNA-array technology. The latter provides the means for the analysis of expression patterns of thousands of genes simultaneously. The use of LCM for proteomics and DNA analysis is also included in this review. These revolutionary approaches are likely to have an unprecedented impact on cancer biology, and provide exciting opportunities to unravel the still-unknown mechanisms involved in squamous cell carcinogenesis. They are also expected to provide a molecular blueprint for HNSCC, thus helping to identify suitable markers for the early detection of preneoplastic lesions, as well as novel targets for pharmacological intervention in this disease.

Carcinoma, Squamous Cell↗
PubMed1994

SORTEZ: a relational translator for NCBI's ASN.1 database.

The National Center for Biotechnology Information (NCBI) has created a database collection that includes several protein and nucleic acid sequence databases, a biosequence-specific subset of MEDLINE, as well as value-added information such as links between similar sequences. Information in the NCBI database is modeled in Abstract Syntax Notation 1 (ASN.1) an Open Systems Interconnection protocol designed for the purpose of exchanging structured data between software applications rather than as a data model for database systems. While the NCBI database is distributed with an easy-to-use information retrieval system, ENTREZ, the ASN.1 data model currently lacks an ad hoc query language for general-purpose data access. For that reason, we have developed a software package, SORTEZ, that transforms the ASN.1 database (or other databases with nested data structures) to a relational data model and subsequently to a relational database management system (Sybase) where information can be accessed through the relational query language, SQL. Because the need to transform data from one data model and schema to another arises naturally in several important contexts, including efficient execution of specific applications, access to multiple databases and adaptation to database evolution this work also serves as a practical study of the issues involved in the various stages of database transformation. We show that transformation from the ASN.1 data model to a relational data model can be largely automated, but that schema transformation and data conversion require considerable domain expertise and would greatly benefit from additional support tools.

Algorithms↗
PubMed1988

A new rhythm library for testing automatic external defibrillators: performance of three devices.

A library of arrhythmias obtained from patients with cardiac arrest was developed. Such a data base will permit both in vitro testing of the rhythm analysis system of automatic external defibrillators before clinical field trials are conducted and comparison of devices. Defibrillators equipped with voice/electrocardiographic tape recorders and used in the prehospital defibrillation programs in Iowa and King County, Washington provided the rhythm source. From these recordings, segments of ventricular fibrillation with minimal artifact and a duration of greater than or equal to 6 s were selected. Segments of ventricular fibrillation (n = 102) were categorized by average peak amplitude as fine (1 to less than 3 mm), medium (3 to less than 7 mm), coarse (7 to less than 12 mm) and extra coarse (greater than or equal to 12 mm), and transcribed onto high fidelity videocassette tapes. Nonventricular fibrillation cardiac arrest rhythms (n = 144), which included wide complex idioventricular rhythms, ventricular and supraventricular tachycardias, asystole and artifact, were also transcribed. Automatic external defibrillators developed by three manufacturers reached a treat (shock) decision on 88 to 93% of the ventricular fibrillation rhythms and on 5 to 10% of the nonventricular fibrillation rhythms. The latter decisions were defined as false positive, though for many rapid nonventricular fibrillation rhythms, countershock may be the appropriate treatment response. There were no statistically significant differences among the three devices in the shock/no shock decisions. A variety of ventricular fibrillation arrhythmias and terminology to express the preclinical performance of automatic external defibrillators are defined. Three commercially available automatic external defibrillators appear to successfully identify ventricular fibrillation and nonventricular fibrillation rhythms.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed2003

Analysis of the Sarcocystis neurona microneme protein SnMIC10: protein characteristics and expression during intracellular development.

Sarcocystis neurona, an apicomplexan parasite, is the primary causative agent of equine protozoal myeloencephalitis. Like other members of the Apicomplexa, S. neurona zoites possess secretory organelles that contain proteins necessary for host cell invasion and intracellular survival. From a collection of S. neurona expressed sequence tags, we identified a sequence encoding a putative microneme protein based on similarity to Toxoplasma gondii MIC10 (TgMIC10). Pairwise sequence alignments of SnMIC10 to TgMIC10 and NcMIC10 from Neospora caninum revealed approximately 33% identity to both orthologues. The open reading frame of the S. neurona gene encodes a 255 amino acid protein with a predicted 39-residue signal peptide. Like TgMIC10 and NcMIC10, SnMIC10 is predicted to be hydrophilic, highly alpha-helical in structure, and devoid of identifiable adhesive domains. Antibodies raised against recombinant SnMIC10 recognised a protein band with an apparent molecular weight of 24 kDa in Western blots of S. neurona merozoites, consistent with the size predicted for SnMIC10. In vitro secretion assays demonstrated that this protein is secreted by extracellular merozoites in a temperature-dependent manner. Indirect immunofluorescence analysis of SnMIC10 showed a polar labelling pattern, which is consistent with the apical position of the micronemes, and immunoelectron microscopy provided definitive localisation of the protein to these secretory organelles. Further analysis of SnMIC10 in intracellular parasites revealed that expression of this protein is temporally regulated during endopolygeny, supporting the view that micronemes are only needed during host cell invasion. Collectively, the data indicate that SnMIC10 is a microneme protein that is part of the excreted/secreted antigen fraction of S. neurona. Identification and characterisation of additional S. neurona microneme antigens and comparisons to orthologues in other Apicomplexa could provide further insight into the functions that these proteins serve during invasion of host cells.

Amino Acid Sequence↗
PubMed2006

Strategies for integrating primary health services in middle- and low-income countries at the point of delivery.

BACKGROUND: Strategies to integrate primary health care aim to bring together inputs, organisation, management and delivery of particular service functions to make them more efficient, and accessible to the service user. In some middle and low income countries, services have been fragmented by separate vertical programmes established to ensure delivery of particular technologies. We examined the effectiveness of integration strategies at the point of delivery. OBJECTIVES: To assess the effects of strategies to integrate primary health care services on producing a more coherent product and improving health care delivery and health status. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care Group specialised register (August 2005), MEDLINE (1966 to September 2005), EMBASE (1988 to 2005), Socio Files (1974 to September 2005), Popline (1970 to September 2005), HealthStar (1975 to September 2005), Cinahl (1982 to September 2005); Cab Health (1972 to 1999), International Bibliography of the Social Sciences (1970 to 1999), and reference lists of articles. We also searched the Internet and World Health Organization (WHO) library database, hand searched relevant WHO publications and contacted experts in the field. SELECTION CRITERIA: Randomised trials, controlled before and after studies, and interrupted time series analyses of integration strategies in primary health care services. Health services in high-income countries were excluded. The primary outcomes were indicators of health care delivery, user views on any measure of service coherence, and health status. We also sought information on comparative costs. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study quality. MAIN RESULTS: Three cluster randomised trials and two controlled before and after studies were included, with three types of comparison: integration by adding on an additional component to an existing service (family planning); integrated services versus single special services (for sex workers); integrated delivery systems versus a vertical service (for family planning); and packages of enhanced primary child care services (integrated management of childhood illnesses) vs. routine child care. Interventions were complex and in some studies inputs varied substantially between comparison arms. Overall, no consistent pattern emerged. Only one study attempted to assess the user's view of the service provided. AUTHORS' CONCLUSIONS: Few studies of good quality, large and with rigorous study design have been carried out to investigate strategies to promote service integration in low and middle income countries. All describe the service supply side, and none examine or measure aspects of the demand side. Future studies must also assess the client's view, as this will influence uptake of integration strategies and their effectiveness on community health.

Child↗
PubMed2006

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.

BACKGROUND: A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and death. The standard treatment to close a PDA is indomethacin. Its use is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has been shown to be effective in closing a PDA without reducing blood flow velocity to the brain, gut or kidneys. OBJECTIVES: To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants. SEARCH STRATEGY: Randomized controlled trials comparing prophylactic ibuprofen use with placebo/no intervention/indomethacin were identified by searching the Cochrane Central Register of Controlled Trial (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966-July 2005), CINAHL (1982-July 2005), EMBASE (1980-July 2005), reference lists of published trials and abstracts published in Pediatric Research (1990-July 2005). No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing use of ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) for the prevention of PDA in preterm and/or low birth weight infants. DATA COLLECTION AND ANALYSIS: Data regarding the clinical outcomes including presence of PDA on day three and day seven, need for surgical ligation, need for rescue treatment with cyclo-oxygenase inhibitors, IVH, mortality, renal and gastrointestinal complications were extracted. Meta-analyses were performed using RevMan 4.2 and treatment estimates were reported as weighted mean difference (WMD), typical relative risk (RR), typical risk difference (RD) and, if statistically significant, number needed to treat (NNT) or number needed to harm (NNH), along with their 95% confidence intervals (CI). MAIN RESULTS: Four trials (n = 672) were included in the review. There was a statistically significant decrease in the incidence of PDA on day three in the ibuprofen group [typical RR 0.37 (95% CI 0.29, 0.49); typical RD -0.29 (95% CI -0.35, -0.22); NNT 3 (95% CI 3, 5); 4 trials, n = 672], in the need for rescue treatment with cyclo-oxygenase inhibitors [typical RR 0.17 (95% CI 0.11, 0.27), typical RD -0.27 (95% CI -0.35, -0.22); NNT 4 (95%CI 3, 5), and in the need for surgical ligation [typical RR 0.34 (95% CI 0.14, 0.81), typical RD -0.04 (95% CI -0.07, -0.01); NNT 25 (95% CI 14, 100). The PDA had closed spontaneously by day three in 60% of the neonates in the control group. There was a significant increase in the serum creatinine levels in the ibuprofen group [WMD 0.13 mg/dl (95% CI 0.08, 0.17); 2 trials, n = 495]. Ibuprofen reduces urine output. There were no statistically significant differences in mortality, grade 3/4 intraventricular hemorrhage, chronic lung disease at 28 days or 36 weeks, necrotizing enterocolitis , gastrointestinal hemorrhage, intestinal perforation or time to reach full feeds. One trial (Gournay 2002) (n = 135) reported on three infants in the ibuprofen group who developed pulmonary hypertension responsive to nitric oxide treatment. AUTHORS' CONCLUSIONS: Prophylactic use of ibuprofen reduces the incidence of PDA, the need for rescue treatment with cyclo-oxygenase inhibitors and surgical closure. However, in the control group, the PDA had closed spontaneously by day three in 60% of the neonates. Prophylactic treatment therefore exposes a large proportion of infants unnecessarily to a drug that has important side effects (mainly involving the kidneys) without conferring any important short term benefits. Prophylactic treatment with ibuprofen is not recommended. Until long-term follow-up results are published from the trials included in this review, no further trials of prophylactic ibuprofen are recommended.

Cyclooxygenase Inhibitors↗
PubMed2006

Transcriptome analysis of the salivary glands of Dermacentor andersoni Stiles (Acari: Ixodidae).

Amongst blood-feeding arthropods, ticks of the family Ixodidae (hard ticks) are vectors and reservoirs of a greater variety of infectious agents than any other ectoparasite. Salivary glands of ixodid ticks secrete a large number of pharmacologically active molecules that not only facilitate feeding but also promote establishment of infectious agents. Genomic, proteomic and immunologic characterization of bioactive salivary gland molecules are, therefore, important as they offer new insights into molecular events occurring at the tick-host interface and they have implications for development of novel control strategies. The present work uses complementary DNA (cDNA) sequence analysis to identify salivary gland transcripts expressed by the Rocky Mountain wood tick, Dermacentor andersoni, a vector of the human pathogens causing Rocky Mountain spotted fever, Colorado tick fever, tularemia, and Powassan encephalitis as well as the veterinary pathogen Anaplasma marginale. Dermacentor andersoni is also capable of inducing tick paralysis. Automated single-pass DNA sequencing was conducted on 1440 randomly selected cDNA clones from the salivary glands of adult female D. andersoni collected during the early stages of feeding (18-24h). Analysis of the expressed sequence tags (ESTs) resulted in 544 singletons and 218 clusters with more than one quality read and attempts were made to assign putative functions to tick genes based on amino acid identity to published protein databases. Approximately 25.6% (195) of the sequences showed limited or no homology to previously identified gene products. A number of novel sequences were identified which presented significant sequence similarity to mammalian genes normally associated with extracellular matrix (ECM), regulation of immune responses, tumor suppression, and wound healing. Several coding sequences possessed various degrees of homology to previously described proteins from other tick species. Preliminary nucleotide variation analysis of these and other tick sequences suggests extensive nucleotide diversity, which has implications for evolution of tick feeding. Intra-species diversity studies can be a promising tool for identifying sequence variations potentially associated with phenotypic traits affecting vector-host-pathogen interactions.

Amino Acid Sequence↗
PubMed1997

Polycystin: in vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane-associated protein.

The primary structure of polycystin predicts a large integral membrane protein with multiple cell recognition motifs, but its function remains unknown. Insight into polycystin's normal function and its role in the development of autosomal dominant polycystic kidney disease (PKD1) requires the assembly of an extensive collection of molecular reagents to examine its expression and create model systems for functional studies. Development of these crucial reagents has been complicated due to the presence of transcriptionally active homologous loci. We have assembled the authentic full-length PKD1 cDNA and demonstrated expression of polycystin in vitro. Polyclonal antibodies directed against distinct extra- and intracellular domains specifically immunoprecipitated in vitro translated polycystin. The panel of antibodies was used to determine localization of polycystin in renal epithelial and endothelial cell lines and tissues of fetal, adult, and cystic origins. In normal adult kidney and maturing fetal nephrons, polycystin expression was confined to epithelial cells of the distal nephron and vascular endothelial cells. Expression in the proximal nephron was only observed after injury-induced cell proliferation. Polycystin expression was confined to ductal epithelium in liver, pancreas, and breast, and restricted to astrocytes in normal brain. We report clear evidence for the membrane localization of polycystin by both tissue sections and by confocal microscopy in cultured renal and endothelial cells. Interestingly, when cultured cells made cell-cell contact, polycystin was localized to the lateral membranes of cells in contact. These data suggest that polycystin is likely to have a widespread role in epithelial cell differentiation and maturation and in cell-cell interactions.

Adult↗
PubMed2006

Transcriptome analyses of human genes and applications for proteome analyses.

By utilizing recently developed full-length cDNA technologies, large-scale cDNA sequencing was carried out by several cDNA projects. Now full-length cDNA resources cover the major part of the protein-coding human genes. Comprehensive analyses of the collected full-length cDNA data revealed not only the complete sequences of thousands of novel gene transcripts but also novel alternatively spliced isoforms of hitherto identified genes. However, it was not as easy as expected to deduce their encoded amino acid sequences based solely on the full-length cDNA sequences. It was neither always the case that the longest open reading frame corresponded to the real protein coding region nor that the first ATG was the translation initiator codon. Also, proteome-wide mass-spectrometry analysis has shown that there is an unexpectedly large population of small proteins, encoded by so-called upstream open reading frames, within the cell. Since sound manual annotations by experts were still indispensable to address these problems, an international meeting to make transcriptome-wide functional annotations of cDNAs was held, namely the H-invitational. In this meeting, functional annotations were made both manually and computationally for most of the pre-existing full-length cDNAs collected from world-wide cDNA projects. The achieved integrated information for each of the cDNAs was published as a database. It was also shown that the full-length cDNA data were useful for identifying alternative splicing variants, exact transcriptional start sites of the mRNAs and the adjacent promoter regions. Rapidly accumulating genome data as well as versatile use of the transcriptome information will shortly lay a firm foundation for proteome-level understanding of human gene networks.

Alternative Splicing↗
PubMed2005

Cognitive behavioural therapy for anxiety disorders in children and adolescents.

BACKGROUND: Childhood and adolescent anxiety disorders are relatively common, occurring in between 5-18% of all children and adolescents. They are associated with significant morbidity and impairment in social and academic functioning, and when persistent, there is a risk of depression, suicide attempts and substance abuse in adulthood. There is accumulating evidence for the efficacy of cognitive behavioural therapy (CBT), with a number of randomised controlled trials (RCTs) suggesting benefit. OBJECTIVES: To determine whether CBT is an effective treatment for childhood and adolescent anxiety disorders in comparison to waiting list or attention controls. SEARCH STRATEGY: Search of the Cochrane Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register, which includes relevant randomised controlled trials from the bibliographic databases - The Cochrane Library ( to January 2004), EMBASE, (1970-2004) MEDLINE (1970-2004) and PsycINFO (1970-2004). We also searched the references of all included studies and relevant textbooks, and contacted authors in order to identify further trials. SELECTION CRITERIA: . Each identified study was assessed for possible inclusion by two reviewers independently. Inclusion criteria consisted of randomised controlled trials of CBT versus waiting list/attention controls in children (more than six years of age) and adolescents (under the age of 19 years) with a DSM (Diagnostic Statistical Manual) or ICD (International Classification of Diseases) anxiety diagnosis; and excluding simple phobia, obsessive compulsive disorder and post-traumatic stress disorder. Each study was required to conform to the principles of CBT through use of a protocol and comprising at least eight sessions of CBT. DATA COLLECTION AND ANALYSIS: The methodological quality of included trials was assessed by two reviewers independently. The dichotomous outcome of remission of anxiety diagnosis was pooled using relative risk (RR) with 95% confidence intervals. Means and standard deviations of anxiety symptom continuous scores were pooled using the standardised mean difference (SMD). Heterogeneity was assessed and intention-to-treat (ITT) analyses undertaken. The presence of publication bias was assessed using funnel plots. MAIN RESULTS: Thirteen studies with 498 subjects and 311 controls met the inclusion criteria and were included in the analyses. The studies involved community or outpatient subjects only, with anxiety of only mild to moderate severity. ITT analyses showed a response rate for remission of any anxiety diagnosis of 56% for CBT versus 28.2% for controls (RR 0.61,95%CI 0.53 to 0.69), with no evidence of heterogeneity. The number needed to treat (NNT) was 3.0 (95%CI 2.5 to 4.5). For reduction in anxiety symptoms, the SMD was -0.58 (95% CI 0.76 to -0.40) with no significant heterogeneity indicated. Individual, group and family/parental formats of CBT produced fairly similar outcomes. AUTHORS' CONCLUSIONS: Cognitive behavioural therapy appears an effective treatment for childhood and adolescent anxiety disorders in comparison to waiting list or attention control. There was no evidence for a difference between an individual, group or parental/family format. CBT can be recommended for the treatment of childhood and anxiety disorders, although with only just over half improving, there is a need for further therapeutic developments.

Adolescent↗
PubMed2004

Percutaneous transluminal angioplasty and stenting for carotid artery stenosis.

BACKGROUND: Carotid artery stenosis may be treated endovascularly by percutaneous transluminal balloon angioplasty with or without stent insertion or by primary stenting. Endovascular treatment may be a useful alternative to carotid endarterectomy (CEA), particularly for lesions not suitable for surgery. OBJECTIVES: The objective of this review was to assess the benefits and risks of endovascular treatments compared with carotid endarterectomy (in patients suitable for surgery) or medical therapy (in patients not suitable for surgery). SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched 1 September 2003). In addition we searched the following bibliographic databases: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2002), MEDLINE (1966 to June 2003), EMBASE (1980 to June 2003) and Science Citation Index (1981 to June 2003). We also contacted researchers in the field and balloon catheter and stent manufacturers. SELECTION CRITERIA: We selected randomised trials of carotid endovascular treatment compared with carotid endarterectomy, or endovascular treatment plus best medical therapy compared with best medical therapy alone, in patients with symptomatic or asymptomatic carotid artery stenosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, extracted data and assessed trial quality. MAIN RESULTS: Two completed trials comparing endovascular treatment with carotid endarterectomy involving 608 patients were found. In addition there were two trials which fulfilled the inclusion criteria and which were stopped early (242 patients), and a third trial which has completed randomisation and 30 day follow up of 307 patients. Four trials are ongoing. Meta analysis of the data from the included studies found no significant difference between the odds of death or any stroke at 30 days post procedure (Odds Ratio [OR] endovascular:surgery 1.26, 95% Confidence Interval [CI] 0.82 to 1.94). The odds of death or disabling stroke at 30 days were similar in the endovascular and surgical group (OR 1.22, CI 0.61 to 2.41). At one year following procedure, there was no significant difference between the two groups in preventing any stroke or death (OR 1.36,CI 0.87 to 2.13). Endovascular treatment significantly reduced the risk of cranial neuropathy (OR 0.12, CI 0.06 to 0.25). There was no significant difference between the two groups when the risk of death, any stroke or myocardial infarction was considered (OR 0.99, CI 0.66 to 1.48). There was substantial heterogeneity between the trials for four of the five outcomes. REVIEWERS' CONCLUSIONS: Data from randomised trials comparing endovascular treatment for carotid artery stenosis with carotid endarterectomy suggest that the two treatments have similar early risks of death or stroke and similar long term benefits. However, the substantial heterogeneity renders the overall estimates of effect somewhat unreliable. Furthermore, two trials were stopped early because of safety concerns, so perhaps leading to an over-estimate of the risks of endovascular treatment. On the other hand, endovascular treatment appears to avoid completely the risk of cranial neuropathy. There is also uncertainty about the potential for restenosis to develop and cause recurrent stroke after endovascular treatment. The current evidence does not support a widespread change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis. There is a strong case to continue recruitment in the current randomised trials comparing carotid stenting with endarterectomy.

Angioplasty, Balloon↗
PubMed2003

G-CSF and GM-CSF for treating or preventing neonatal infections.

BACKGROUND: The colony stimulating factors (CSFs), granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF), are naturally occurring cytokines that stimulate the production and antibacterial function of neutrophils and monocytes. Two strategies have been adopted for exploring whether CSFs can provide clinical benefit for preterm infants. The first has investigated their use as a treatment to improve outcome in established systemic infection, especially when complicated by a low neutrophil count. The alternative strategy has been to use CSFs prophylactically, to prevent sepsis prospectively through stimulation of neutrophil production and bactericidal function. OBJECTIVES: To determine the efficacy and safety of the haemopoietic colony stimulating factors (G-CSF or GM-CSF) in newborn infants, when used for:a) treatment of suspected or proven systemic infection to reduce mortality, orb) prophylaxis, to prevent systemic infection in infants at high risk of nosocomial infection. To determine, in subgroup analysis, the influence of pre-existing or high risk of neutropenia on the outcome of therapy. SEARCH STRATEGY: PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003) were searched in April 2003 using the keywords: G-CSF, GM-CSF, infant newborn, with and without the limit Clinical Trial. In addition, reference lists of identified RCTs, meta-analyses and personal files were searched. SELECTION CRITERIA: The criteria used to select studies for inclusion were: DESIGN: RCT. SUBJECTS: Newborn infants in intensive care. INTERVENTIONS: G-CSF or GM-CSF given as treatment in conjunction with antibiotics for suspected or microbiologically proven systemic infection. G-CSF or GM-CSF given as prophylaxis with the aim of reducing the incidence of systemic infection. OUTCOMES: Treatment studies reporting all cause mortality. Prophylaxis studies reporting subsequent incidence of sepsis and / or mortality. DATA COLLECTION AND ANALYSIS: Relative risks (RR) and risk differences (RD) with 95% confidence intervals (CI) using the fixed effect model are reported. Number needed to treat (NNT) was calculated for the outcomes that showed a statistically significant reduction in RR. MAIN RESULTS: Seven treatment studies of 257 infants with suspected systemic bacterial infection and three prophylaxis studies comprising 359 neonates are analysed. Treatment studies: There is no evidence that the addition of G-CSF or GM-CSF to antibiotic therapy in preterm infants with suspected systemic infection reduces immediate all cause mortality. No significant survival advantage was seen at 14 days from the start of therapy [typical RR 0.71 (95% CI 0.38,1.33); typical RD -0.05 (95% CI -0.14, 0.04)]. However all seven of the treatment studies were small, the largest recruiting only 60 infants. The subgroup analysis of 97 infants from three treatment studies who, in addition to systemic infection, had clinically significant neutropenia (< 1.7 x 10(9)/l) at trial entry, does show a significant reduction in mortality by day 14 [RR 0.34 (95% CI 0.12, 0.92); RD -0.18 (95% CI -0.33, -0.03); NNT 6 (95% CI 3-33)]. Prophylaxis studies have not demonstrated a significant reduction in mortality in neonates receiving GM-CSF [RR 0.59 (95% CI 0.24,1.44); RD -0.03 (95% CI -0.08,0.02)]. The identification of sepsis as the primary outcome of prophylaxis studies has been hampered by inadequately stringent definitions of systemic infection. However, data from one study suggest that prophylactic GM-CSF may provide protection against infection when given to preterm infants who are neutropenic or at high risk of developing postnatal neutropenia. REVIEWER'S CONCLUSIONS: There is currently insufficient evidence to support the introduction of either G-CSF or GM-CSF into neonatal practice, either as treatment of established systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high risk neonates. No toxicity of CSF use was reported in any systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high risk neonates. No toxicity of CSF use was reported in any study included in this review. The limited data suggesting that CSF treatment may reduce mortality when systemic infection is accompanied by severe neutropenia should be investigated further in adequately powered trials which recruit sufficient infants infected with organisms associated with a significant mortality risk.

Anti-Bacterial Agents↗
PubMed1995

The availability of health information in South Africa.

The South African Medical Research Council (MRC) has provided access to on-line health and biomedical information since 1976, when the MRC became an international partner of NLM. This was done to support research and health care when the Institute of Biomedical Communication was established. The institute has since reorganized and is now the Information Systems Division in the Research Systems Support Group MRC. he MRC and medical libraries in South Africa are able to access various automated services via telecommunication. The major systems available are MEDLARS, DIALOG, DATASTAR and BRS, with ECRI being the latest addition; most used are MEDLARS and DIALOG. New technologies (e.g., CD-ROM) have given more people access. This technology is not available to many people working in Primary Health Care (PHC), as they do not have access to computer networks. Beyond on-line is statistical and printed information, called "Gray Literature," not accessible through on-line systems as it is not published in conventional sources used to build databases. With a shift to Essential National Health Research and the focus on PHC and preventative medicine, demand for health information and "gray literature" is growing. The MRC collects and produces this material and has its own database called SAMED, which is to be made available to others as our contribution to health. It is hoped to make this available for inclusion in the proposed African Index Medicus presently investigated by the World Health Organization. Africa as a continent, and South Africa as a country, are experiencing major changes in health care and medical practice, and inevitably, provision of health information services. With South Africa's re-entry into the global village and its acceptance by the rest of Africa, it can be a key player in information provision to the rest of the continent. The MRC, as a major provider of Health information, can play a vital role in the information flow throughout Africa by continuously improving and expanding its services. A large proportion of South Africans live in rural areas where health care is provided by clinics not linked to information networks. This does not mean these clinics are excluded from the use of information. The major challenge is to find the ways and means of getting the relevant information to these clinics. Information is needed to help with patient care and continuing education. With this in mind, the MRC is evaluating different formats in which information can be supplied. Due to the lack of computer literacy, facilities, and financial constraints, it is better to supply printed information. With the spread of technology through the country and continent, it can be assumed that information flow and transfer will be more rapid. Repackaging of information means that it is possible to get the relevant information to the right people at the right time. The first such package developed is for hospital managers. With the help from experts in the field of PHC, it is hoped to develop packages aimed specifically at the CHWs and other workers in the field. All packages developed by the MRC are backed by a document provision service, using the most cost-effective route to obtain documents. A printed product must comply with certain criteria; these are: 1) purpose for which the information is needed; 2) kind of information needed and the format in which it is needed; 3) when the information is needed; 4) is the information to be supplied on an ongoing basis i.e., updated with latest information; 5) cost involved; and 6) how to get the information to the relevant user.

Computer Communication Networks↗
PubMed1991

Hepatitis E virus: identification of type-common epitopes.

Large epidemic outbreaks of enterically transmitted non-A, non-B viral hepatitis (ET-NANBH) have been documented in developing countries. A molecular clone derived from the causative agent, the hepatitis E virus (HEV), has recently been described (G.R. Reyes, M.A. Purdy, J.P. Kim, K.-C. Luk, L.M. Young, K.E. Fry, and D. Bradley, Science 247:1335-1339, 1990). We now report the isolation, by serologic screening, of two cDNA clones derived from a fecal sample collected during a 1986 outbreak of ET-NANBH in Telixtac, Mexico. The cDNA clones encode epitopes that specifically reacted with acute- and convalescent-phase sera collected during five different ET-NANBH epidemics and represent the initial cloning of the Mexico strain of HEV. Recombinant fusion proteins expressed from these clones were also recognized by antibodies from cynomolgus macaques experimentally infected with HEV. The cDNA clones were shown to be derived from HEV by their specific hybridization to the previously recognized full-length genomic RNA transcript of approximately 7.5 kb. In addition, however, subgenomic polyadenylated transcripts of approximately 2.0 and approximately 3.7 kb were also identified in HEV-infected cynomolgus monkey liver. Sequences homologous to the epitope clones were isolated from the Burma strain of the virus, and these demonstrated reactivity comparable to that seen with the Mexico strain epitopes. When compared with the available full-length sequence of the Burma strain of HEV, it was discovered that the cDNA clones were encoded in different open reading frames (ORFs). The comparison between Mexico and Burma HEV strains indicated amino acid homologies of 90.5 and 73.5% for these epitope-encoding clones derived from ORF2 and ORF3, respectively. The identification of these clones not only has provided insight into the expression strategy of HEV but has also resulted in a source of recombinant protein useful in the diagnosis of HEV-induced hepatitis.

Amino Acid Sequence↗
PubMed2000

[Development of bioethics. Analysis of practices in 20 hospital departments].

OBJECTIVE: In order to analyze the constitution and management of DNA banks and the limitations on procedures currently used in France, we conducted a study in a sample of French hospital units. A DNA bank was defined as any facility where individual samples of DNA, irrespective of the form, are stored for ongoing or future gene studies. The aim of this work was to focus attention on the need for in-depth thought on the ethical issues involved in storing and using DNA as part of everyday clinical practice and research and to provide elements for a debate on the interest and limitations of the French bioethics laws whose revision is currently being considered. METHODS: A questionnaire was sent to the heads of departments in two university hospitals. Five areas were retained for evaluation: the nature and degree of DNA storage activities, procedures followed for reporting the DNA bank, procedures used to protect confidentiality, information given to patients and procedures used for informed consent, and finally, internal rules governing the bank's operation. The answers to the questionnaires were analyzed anonymously. RESULTS: Among 20 hospital units collecting DNA samples, 70% also stored other samples (DNA, blood, tissue, cell lines) including a large proportion of tissue samples. These samples were collected for purposes of fundamental research and clinical practice. The number of samples stored was quite variable, ranging from a few dozen samples to more than 40,000. Only 55% of the units had reported the facility to a control body, in compliance with current law. Seventy percent maintained computerized data bases but only 50% used an anonymous code. Seventy-five percent obtained written consent but patients were not always informed of the site of the storage or the transfer of their DNA. In addition, the validity of the consent over time, the duration of storage and the types of studies that could be conducted on the DNA were poorly detailed. Internal rules governing the bank's activities were not implemented by most of the units (65%). CONCLUSION: The responses to our questionnaire survey show that there is currently a gap between everyday practice and regulatory procedures concerning DNA banks in France. Further analysis of current practices would appear to be necessary so professionals could become more aware of the human and social issues involved with the use of DNA banks. These data on everyday practices should be made available to health care workers, public officials and law makers in order to promote ethical practices that, as has been observed, are not dictated solely by legislation which often lags behind everyday activities. All those involved in the management of DNA banks must be aware of their responsibilities in protecting patients' rights within the framework of a system based on information, consent, and over-the-board trustworthiness regularly submitted to short and long term assessments. A correct response to ethical issues is the only means of developing a real process of social interaction which cannot be achieved by revision of the bioethics laws alone.

Confidentiality↗
PubMed2000

A high-throughput AFLP-based method for constructing integrated genetic and physical maps: progress toward a sorghum genome map.

Sorghum is an important target for plant genomic mapping because of its adaptation to harsh environments, diverse germplasm collection, and value for comparing the genomes of grass species such as corn and rice. The construction of an integrated genetic and physical map of the sorghum genome (750 Mbp) is a primary goal of our sorghum genome project. To help accomplish this task, we have developed a new high-throughput PCR-based method for building BAC contigs and locating BAC clones on the sorghum genetic map. This task involved pooling 24,576 sorghum BAC clones ( approximately 4x genome equivalents) in six different matrices to create 184 pools of BAC DNA. DNA fragments from each pool were amplified using amplified fragment length polymorphism (AFLP) technology, resolved on a LI-COR dual-dye DNA sequencing system, and analyzed using Bionumerics software. On average, each set of AFLP primers amplified 28 single-copy DNA markers that were useful for identifying overlapping BAC clones. Data from 32 different AFLP primer combinations identified approximately 2400 BACs and ordered approximately 700 BAC contigs. Analysis of a sorghum RIL mapping population using the same primer pairs located approximately 200 of the BAC contigs on the sorghum genetic map. Restriction endonuclease fingerprinting of the entire collection of sorghum BAC clones was applied to test and extend the contigs constructed using this PCR-based methodology. Analysis of the fingerprint data allowed for the identification of 3366 contigs each containing an average of 5 BACs. BACs in approximately 65% of the contigs aligned by AFLP analysis had sufficient overlap to be confirmed by DNA fingerprint analysis. In addition, 30% of the overlapping BACs aligned by AFLP analysis provided information for merging contigs and singletons that could not be joined using fingerprint data alone. Thus, the combination of fingerprinting and AFLP-based contig assembly and mapping provides a reliable, high-throughput method for building an integrated genetic and physical map of the sorghum genome.

Chromosomes, Bacterial↗
PubMed2000

Growth hormone for in vitro fertilization.

BACKGROUND: Ovulation induction protocols for in vitro fertilization (IVF) are constantly under review and revision in an attempt to decrease gonadotropin requirements while improving follicular recruitment and pregnancy rate. Most studies of the effect of Growth Hormone on ovulation induction have investigated normally ovulating infertile women. Attention has begun to turn to its effect on women who fail to produce an optimal number of follicles in response to ovulation induction. OBJECTIVES: To assess the effectiveness of growth hormone adjuvant therapy for women undergoing ovulation induction prior to IVF in two patient groups: a) those with no previous history of poor response and b) those with a history of poor response. SEARCH STRATEGY: This review has drawn on the search strategy developed for the Subfertility Group as a whole. Relevant trials were identified in the Group's Specialised Register of Controlled Trials. See Review Group details for more information. SELECTION CRITERIA: All RCTs were included if they addressed the research question posed and provided outcome data for intervention and control subjects. Outcomes of interest included pregnancy, oocyte/embryo number and peak estradiol level. DATA COLLECTION AND ANALYSIS DATA EXTRACTION: A diverse search strategy was employed, including hand-search of 43 core journals from 1966 to the present, bibliographies of relevant trials, MEDLINE database, abstracts from North American and European meetings and contact with authors of relevant papers. Relevant data were extracted independently by two reviewers using the standardized data extraction sheet. Validity was assessed in terms of method of randomization, completeness of follow-up, presence or absence of crossover and co-intervention. DATA SYNTHESIS: 2x2 tables were generated for all relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique. Statistical heterogeneity was assessed using x2. MAIN RESULTS: In women with no previous history of poor stimulation, the common odds ratio for pregnancy per cycle was 0.97 (95% CI 0.34-2. 76) Total dose of gonadotropin and number of oocytes retrieved were similar between treated and placebo groups. In previous poor responders, the common odds ratio for pregnancy per cycle instituted was 2.55 (95% CI 0.64-10.12). Again, no statistically significant difference was noted in gonadotropin dosage or oocyte number obtained, when all studies were considered. REVIEWER'S CONCLUSIONS: Data from 6 small trials suggest that in women with no previous poor response, GH augmentation does not improve the rate of pregnancy. In poor responders, a trend towards improved outcome with GH treatment deserves further study.

Female↗