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PubMed2005

Volume-targeted versus pressure-limited ventilation in the neonate.

BACKGROUND: Inflammation caused by lung overdistension (volutrauma) is thought to be important in the pathogenesis of bronchopulmonary dysplasia (BPD). Preterm infants with variable lung compliance are particularly at risk. Volume-targeted neonatal ventilators have been developed as alternatives to traditional pressure-limited ventilators. They deliver consistent, appropriate tidal volumes with the aim of reducing lung damage. It is suggested that these would provide an effective, safer means of ventilating the newborn infant. OBJECTIVES: To determine whether volume-targeted ventilation compared with pressure-limited ventilation leads to reduced rates of death and BPD in newborn infants. Secondary objectives were to determine whether use of volume modes affected clinical outcomes such as incidence of airleak, growth, duration of ventilation or cranial ultrasound findings. SEARCH STRATEGY: The search strategy comprised searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), MEDLINE PubMed 1966 to November 2004, and hand searches of reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All randomised and quasi-randomised trials comparing the use of volume-targeted versus pressure-limited ventilation in neonates in the first 28 days of life. DATA COLLECTION AND ANALYSIS: Two authors assessed the methodological quality of eligible trials and extracted data independently. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. For categorical data the relative risk (RR) and risk difference (RD) were calculated with 95% confidence intervals. Number needed to treat was calculated when RD was statistically significant. Continuous data were analysed using weighted mean difference (WMD). MAIN RESULTS: Four randomised trials were identified that addressed the outcomes of this review, recruiting a total of 178 preterm infants. All were recruited during the first 72 hours of life. Caregivers and those evaluating the outcomes of trials were not masked. All trials report high rates of follow-up, although one trial with uneven patient distribution may have had some post-randomisation attrition. No significant difference was found for death by hospital discharge, and no trials reported the combined outcome of death or BPD. When secondary outcomes were examined, pooled analysis of the trials showed that volume-targeted ventilation resulted in significant reductions in duration of ventilation [WMD -2.93 days (-4.28, -1.57)] and rates of pneumothorax [typical RR 0.23 (0.07, 0.76), RD -0.11 (-0.20, -0.03), NNT 9]. There was also a significant difference in rates of severe (Grade 3 or 4) intraventricular haemorrhage favouring the volume-targeted group [typical RR 0.32 (0.11, 0.90), RD -0.16 (-0.29, -0.03), NNT 6]. There was a reduction in the incidence of BPD (supplemental oxygen at 36 weeks) amongst surviving infants, of borderline statistical significance [typical RR 0.34 (0.11, 1.05), RD -0.14 (-0.27, 0.00), NNT=7]. No significant differences were found for failure of mode of ventilation, use of neuromuscular paralysis, patent ductus arteriosus, airleak of any sort or pulmonary interstitial emphysema alone, cranial ultrasound abnormalities or periventricular leucomalacia. None of the trials addressed growth, death after discharge from hospital or neurodevelopmental outcome. AUTHORS' CONCLUSIONS: Although rates of death and BPD were not significantly different between the two ventilator strategies, statistically significant effects favouring volume targeting were shown for some clinically important outcomes. However, the numbers of trials and infants randomised are small and further studies are required to confirm the role of volume targeting in neonatal ventilation.

Bronchopulmonary Dysplasia↗
PubMed2025

SLB-msSIM: A Spectral Library-Based Multiplex Segmented SIM Platform for Single-Cell Proteomic Analysis.

Mass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by a multiplex segmented selected ion monitoring (msSIM) technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a single scan in the Orbitrap. Proteomic identification is achieved through spectral matching using a well-defined spectral library. We applied the SLB-msSIM method to interrogate cellular heterogeneity in various pancreatic cancer cell lines, revealing common and distinct functional traits among PANC-1, MIA-PaCa2, AsPc-1, HPAF, and normal HPDE cells. Furthermore, for the first time, our novel data revealed the diverse cell trajectories of individual PANC-1 cells during the induction and reversal of epithelial-mesenchymal transition (EMT). Collectively, our results demonstrate that SLB-msSIM is a highly sensitive and robust platform, applicable to a wide range of instruments for single-cell proteomic studies. SUMMARY: We present the SLB-msSIM method, a conceptually unique approach in mass spectrometry-based single-cell proteomics that significantly enhances sensitivity and robustness. This innovative platform enables detailed analysis of the proteome landscape, capturing cellular heterogeneity, trajectories, and phenotypes at a single-cell resolution. Utilizing the SLB-msSIM technique, we identified both common and distinct functional traits among various pancreatic cancer cell lines and normal cells. Moreover, our study unveiled new insights into the diverse cell trajectories of individual cancer cells during the induction and reversal of epithelial-mesenchymal transition (EMT). In summary, the SLB-msSIM method offers a highly sensitive and robust platform for single-cell proteomic studies, with broad applicability across different instruments.

Single-Cell Analysis↗
PubMed2002

Reliability of logP predictions based on calculated molecular descriptors: a critical review.

Correct QSAR analysis requires reliable measured or calculated logP values, being logP the most frequently utilized and most important physico-chemical parameter in such studies. Since the publication of theoretical fundamentals of logP prediction, many commercial software solutions are available. These programs are all based on experimental data of huge databases therefore the predicted logP values are mostly acceptable - especially for known structures and their derivatives. In this study we critically reviewed the published methods and compared the predictive power of commercial softwares (CLOGP, KOWWIN, SciLogP/ULTRA) to each other and to our recently developed automatic QS(P)AR program. We have selected a very diverse set of 625 known drugs (98%) and drug-like molecules with experimentally validated logP values. We have collected 78 reported "outliers" as well, which could not be predicted by the "traditional" methods. We used these data in the model building and validation. Finally, we used an external validation set of compounds missing from public databases. We emphasized the importance of data quality, descriptor calculation and selection, and presented a general, reliable descriptor selection and validation technique for such kind of studies. Our method is based on the strictest mathematical and statistical rules, fully automatic and after the initial settings there is no option for user intervention. Three approaches were applied: multiple linear regression, partial least squares analysis and artificial neural network. LogP predictions with a multiple linear regression model showed acceptable accuracy for new compounds therefore it can be used for "in-silico-screening" and/or planning virtual/combinatorial libraries.

Combinatorial Chemistry Techniques↗
PubMed2004

Non-steroidal anti-inflammatory drugs for preventing heterotopic bone formation after hip arthroplasty.

BACKGROUND: Heterotopic bone formation (HBF) in the soft tissues surrounding the hip joint is a frequent complication of hip surgery. Non-steroidal anti-inflammatory drugs (NSAIDs) administered in the immediate perioperative period reduce the risk of HBF. However, the magnitude of the effect on HBF, and the effects on other associated outcomes, such as pain and physical function, are uncertain. OBJECTIVES: To determine the effects of perioperative NSAID therapy versus control on the risk of HBF and other outcomes in patients undergoing hip arthroplasty. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Injuries Group specialised register (October 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 3, 2002), MEDLINE (1966 to October 2002), EMBASE (1988 to 2002 Week 43), CURRENT CONTENTS (1993 Week 27 to 2002 Week 44) and reference lists of articles. We also contacted trialists and drug manufacturers. SELECTION CRITERIA: All trials which enrolled patients scheduled to undergo hip arthroplasty with random or quasi-random allocation to perioperative NSAID or control and that recorded post-operative radiographically determined HBF. The primary outcome was post-operative radiographic HBF. Secondary outcomes were pain, function (including range of motion), gastro-intestinal and other bleeding complications, and other causes of major morbidity or mortality. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed methodological quality and extracted data. All analyses were conducted on dichotomised outcomes. MAIN RESULTS: Sixteen randomised and two quasi-randomised trials involving a total of 4,763 patients were included. Overall, in 17 trials that examined the effects of medium to high doses of NSAIDs, there was a reduced risk of developing HBF after hip surgery (59% reduction, 95% confidence interval 54% to 64% reduction). In contrast, one large trial examining low-dose aspirin, demonstrated no effect on the risk of HBF (2% reduction, 95% confidence interval 15% reduction to 12% increase). There was strong evidence of differences in the size of the treatment effects observed between the trials examining medium to high doses of NSAIDs, but reasons were not clearly identified. There was a non-significant one third increased risk of gastro-intestinal side effects among patients assigned NSAIDs (29% increase, 95% confidence interval 0% to 76% increase). Most of this increase was due to an increased risk of minor gastro-intestinal complications. Data on the late post-operative outcomes of pain, impaired physical function and range of joint movement were few and no formal overviews of the effects of NSAIDs on these outcomes were possible. REVIEWERS' CONCLUSIONS: Perioperative NSAIDs, apart from low dose aspirin, appear to produce between a one half and two thirds reduction in the risk of HBF. With routine use, such agents may be able to prevent 15-20 cases of HBF among every 100 total hip replacements performed. However, while medium to high doses of perioperative NSAIDs clearly produce a substantial reduction in the incidence of radiographic HBF, there remains some uncertainty about short-term side effects of treatment and substantial uncertainty about effects on long-term clinical outcomes such as chronic pain and impaired physical function. The net effect of routine HBF prophylaxis with NSAIDs requires formal assessment in a randomised trial designed to determine the balance of benefits and risks for all outcomes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection.

BACKGROUND: Embryo transfer (ET) was traditionally performed two days after oocyte retrieval; however, developments in culture media have allowed embryos to be maintained in culture for longer periods. Delaying transfer from day two to day three would allow for further development of the embryo and might have a positive effect on pregnancy outcomes. OBJECTIVES: To determine if there is any difference in live birth and pregnancy rates when ET is performed on day three, compared with day two, in infertile couples undergoing treatment with in vitro fertilization (IVF), including intracytoplasmic sperm injection (ICSI). SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (17th December 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to 2003), EMBASE (1980 to 2003) and Biological Abstracts Databases (1980 to 2003), the National Research Register (NRR), the Medical Research Council's Clinical Trials Register, the NHS Centre for Reviews and Dissemination, citation lists of relevant publications, review articles and included studies, as well as abstracts of appropriate scientific meetings. SELECTION CRITERIA: Randomized controlled trials that compared day three versus day two embryo transfer after oocyte retrieval during an IVF or ICSI treatment cycle in subfertile couples. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. The primary outcome measures were live birth rate and ongoing pregnancy rate. MAIN RESULTS: Ten studies involving 2027 women were included, but only three studies reported live birth and four reported ongoing pregnancy rates. The pooled odds ratios (day three compared to day two) were 1.07, 95% CI 0.84 to 1.37 for live birth and 1.05, 95% CI 0.83 to 1.32 for ongoing pregnancy. From ten studies, the pooled odds ratio for clinical pregnancy was 1.26, 95% CI 1.06 to 1.51. Sub-group analysis revealed that this advantage occurred in those undergoing ICSI cycles. A higher miscarriage rate with day 3 ET in ICSI cycles works to negate the increased clinical pregnancy rate, in agreement with the finding of no significant difference between treatments in live birth rate. REVIEWERS' CONCLUSIONS: Although an increase in clinical pregnancy rate with day three embryo transfer was demonstrated, at present there is not sufficient good quality evidence to suggest an improvement in live birth when embryo transfer is delayed from day two to day three.

Embryo Transfer↗
PubMed2006

Pneumococcal vaccination during pregnancy for preventing infant infection.

BACKGROUND: Each year at least one million children worldwide die of pneumococcal infections. The development of bacterial resistance to antimicrobials adds to the difficulty of treatment of diseases and emphasizes the need for a preventive approach. Newborn vaccination schedules could substantially reduce the impact of pneumococcal disease in immunized children, but does not have an effect on the morbidity and mortality of infants less than three months of age. Pneumococcal vaccination during pregnancy may be a way of preventing pneumococcal disease during the first months of life before the pneumococcal vaccine administered to the infant starts to produce protection. OBJECTIVES: To assess the effect of pneumococcal vaccination during pregnancy for preventing infant infection. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (June 2004), CENTRAL (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to June 2004), EMBASE (January 1985 to June 2004), and reference lists of articles. SELECTION CRITERIA: Randomized controlled trials in pregnant women comparing pneumococcal vaccine with placebo or doing nothing or with another vaccine to prevent infant infections. DATA COLLECTION AND ANALYSIS: Two authors independently assessed methodological quality and extracted data using a data collection form. Study authors were contacted for additional information. MAIN RESULTS: Three trials (280 participants) were included. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (one trial, 149 pregnancies, relative risk (RR) 0.51; 95% confidence interval (CI) 0.18 to 1.41). Although the data suggest an effect in reducing pneumococcal colonisation in infants by 16 months of age (one trial, 56 pregnancies, RR 0.33; 95% CI 0.11 to 0.98), there was no evidence of this effect in infants at two months of age (RR 0.28; 95% CI 0.02 to 5.11) or by seven months of age (RR 0.32; 95% CI 0.08 to 1.29). AUTHORS' CONCLUSIONS: There is insufficient evidence to support whether pneumococcal vaccination during pregnancy could reduce infant infections.

Female↗
PubMed2001

Towards a genetic-based classification of human lung cancer.

Lung cancer is a highly aggressive neoplasm which is reflected by a multitude of genetic aberrations being detectable on the chromosomal and molecular level. In order to understand this seemingly genetic chaos, we performed Comparative Genomic Hybridisation (CGH) in a large collective of human lung carcinomas investigating different tumor entities as well as multiple individual tumour specimens of single patients. Despite the considerable genetic instability being reflected by the well known morphological heterogeneity of lung cancer the comparison of different tumour groups using custom made computer software revealed recurrent aberration patterns and highlighted chromosomal imbalances that were significantly associated with morphological histotypes and biological phenotypes. Specifically we identified imbalances in NSCLC being associated with metastasis formation which are typically present in SCLC thus explaining why the latter is such an aggressive neoplasm characterized by widespread tumor dissemination. Based on the genetic data a new model for the development of SCLC is presented. It suggests that SCLC evolving from the same stem cell as NSCLC should be differentiated into primary and secondary tumors. Primary SCLC corresponding to the classical type evolved directly from an epithelial precursor cell. In contrast, secondary SCLC correlating with the combined SCLC develops via an NSCLC intermediate. In addition, we established libraries of differentially expressed genes from different human lung cancer types to identify new candidate genes for several of the chromosomal subregions identified by CGH. In this review, we summarise the status of our results aiming at a refined classification of lung cancer based on the pattern of genetic aberrations.

Carcinoma, Non-Small-Cell Lung↗
PubMed1992

Mapping human chromosomes by walking with sequence-tagged sites from end fragments of yeast artificial chromosome inserts.

Sequence-tagged sites (STSs) derived from end fragments of chromosome-specific yeast artificial chromosomes (YACs) can facilitate the assembly of an overlapping YAC/STS map. Contigs form rapidly by iteratively screening YAC collections with end-fragment STSs from YACs that have not yet been detected by any previous STS. The map is rendered rapidly useful during its assembly by incorporating supplementary STSs from genes and genetic linkage probes with known locations. Methods for the systematic development and testing of the end-fragments STSs are given here, and a group of 100 STSs is presented for the X chromosome. The mapping strategy is shown to be successful in simulations with portions of the X chromosome already largely mapped into overlapping YACs by other means.

Base Sequence↗
PubMed2006

Recombinant human activated protein C for severe sepsis in neonates.

BACKGROUND: Sepsis is a common problem in both preterm and term infants. Although the overall incidence of neonatal sepsis has declined over the past decade, mortality remains high. Recombinant human activated protein C (rhAPC) has been shown to possess a broad spectrum of activity modulating coagulation and has been shown in septic adults to reduce mortality. In septic children, an open label study has shown similar pharmacokinetics, adverse reaction profile and frequency as in adults with severe sepsis. OBJECTIVES: To determine whether treatment with rhAPC will reduce mortality and/or morbidity in neonates with severe sepsis. SEARCH STRATEGY: Searches were carried out in July 2005 by the review authors independently of MEDLINE (1966 to July 2005), EMBASE (1980 to July 2005), CINAHL (1982 to July 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), abstracts of annual meetings of the Pediatric Academic Societies and Society for Pediatric Research which were published in Pediatric Research from 1980, and contacts were made with subject experts. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched from 1980. No language restriction was applied. SELECTION CRITERIA: Studies were included if they were randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials were required to report treatment effects on at least one of the following outcomes: all cause mortality during initial hospital stay, neurological development and neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease in survivors, periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events. DATA COLLECTION AND ANALYSIS: Both review authors independently evaluated the papers for inclusion criteria and quality, and abstracted information for the outcomes of interest. Differences were resolved by mutual discussion. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effects model was to be used for meta-analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data. MAIN RESULTS: No eligible trials were identified. AUTHORS' CONCLUSIONS: Despite the scientific rationale for its use, there are insufficient data to support the use of rhAPC for the management of severe sepsis in newborn infants. There is a need for large well-designed trials to elucidate the effectiveness of rhAPC to reduce mortality and adverse outcomes in neonates with severe sepsis. The results of such trials would guide clinical practice. Currently, a cautious approach to the use of rhAPC is warranted due to the high incidence of bleeding with its use; especially as severe sepsis in preterm infants is commonly associated with bleeding problems and intraventricular hemorrhage. Its use is not recommended outside of randomized controlled trials.

Humans↗
PubMed2005

JAtlasView: a Java atlas-viewer for browsing biomedical 3D images and atlases.

BACKGROUND: Many three-dimensional (3D) images are routinely collected in biomedical research and a number of digital atlases with associated anatomical and other information have been published. A number of tools are available for viewing this data ranging from commercial visualization packages to freely available, typically system architecture dependent, solutions. Here we discuss an atlas viewer implemented to run on any workstation using the architecture neutral Java programming language. RESULTS: We report the development of a freely available Java based viewer for 3D image data, descibe the structure and functionality of the viewer and how automated tools can be developed to manage the Java Native Interface code. The viewer allows arbitrary re-sectioning of the data and interactive browsing through the volume. With appropriately formatted data, for example as provided for the Electronic Atlas of the Developing Human Brain, a 3D surface view and anatomical browsing is available. The interface is developed in Java with Java3D providing the 3D rendering. For efficiency the image data is manipulated using the Woolz image-processing library provided as a dynamically linked module for each machine architecture. CONCLUSION: We conclude that Java provides an appropriate environment for efficient development of these tools and techniques exist to allow computationally efficient image-processing libraries to be integrated relatively easily.

Anatomy↗
PubMed2003

Informatics center for mouse genomics: the dissection of complex traits of the nervous system.

In recent years, there has been an explosion in the number of tools and techniques available to researchers interested in exploring the genetic basis of all aspects of central nervous system (CNS) development and function. Here, we exploit a powerful new reductionist approach to explore the genetic basis of the very significant structural and molecular differences between the brains of different strains of mice, called either complex trait or quantitative trait loci (QTL) analysis. Our specific focus has been to provide universal access over the web to tools for the genetic dissection of complex traits of the CNS--tools that allow researchers to map genes that modulate phenotypes at a variety of levels ranging from the molecular all the way to the anatomy of the entire brain. Our website, The Mouse Brain Library (MBL; http://mbl.org) is comprised of four interrelated components that are designed to support this goal: The Brain Library, iScope, Neurocartographer, and WebQTL. The centerpiece of the MBL is an image database of histologically prepared museum-quality slides representing nearly 2000 mice from over 120 strains--a library suitable for stereologic analysis of regional volume. The iScope provides fast access to the entire slide collection using streaming video technology, enabling neuroscientists to acquire high-magnification images of any CNS region for any of the mice in the MBL. Neurocartographer provides automatic segmentation of images from the MBL by warping precisely delineated boundaries from a 3D atlas of the mouse brain. Finally, WebQTL provides statistical and graphical analysis of linkage between phenotypes and genotypes.

Analysis of Variance↗
PubMed2003

Corticosteroids for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), also called cryptogenic fibrosing alveolitis (CFA), is a lethal form of diffuse lung disorder of unknown origin; the mean survival being two to four years. Currently recommended and most prescribed therapy for IPF is based on the use of systemic corticosteroids, even if no formal demonstration of efficacy of this treatment of IPF is available. Furthermore, new insights from pathological studies have produced a new hypothesis, based upon the central role played by aberrant wound healing following repeated lung injury, weakening the rationale basis of the use of corticosteroids in IPF, previously considered simply a chronic inflammatory disease. OBJECTIVES: The objective of the review was to determine the efficacy of corticosteroids in the treatment of adults with IPF. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2002), MEDLINE (January 1966 to May 2002) and EMBASE (January 1985 to December 2002) and reference lists of articles. We searched reference lists of published articles to identify trials. SELECTION CRITERIA: Randomised controlled trials (RCT) and controlled clinical trials (CCT) using corticosteroids alone for the treatment of adults with IPF. DATA COLLECTION AND ANALYSIS: Abstracts of identified articles were retrieved and articles possibly fulfilling inclusion criteria were retrieved in full. Two reviewers would have independently assessed trial quality if there had been any included studies. MAIN RESULTS: Fifteen studies were selected as potentially eligible for meta-analysis. After further analysis of full text papers, no RCTs or CCTs were identified as suitable and therefore no data was available for inclusion in any meta-analysis. All studies were excluded due to inadequate methodologies. REVIEWER'S CONCLUSIONS: At present, there is no evidence for an effect of corticosteroid treatment in patients with Idiopathic pulmonary fibrosis(IPF)/usual interstitial pneumonia (UIP). Given developments in understanding of the pathogenesis of IPF, randomised controlled trials designed to test the efficacy of corticosteroids will probably never be designed. As other forms of pulmonary fibrosis such as non-specific interstitial pneumonia are reported to show a better response to corticosteroids, it is crucial to make an accurate diagnosis in each patient. Moreover, therapies with immunomodulatory rather than anti-inflammatory or immunosuppressive effects may be more promising for the effective treatment of IPF/UIP.

Adrenal Cortex Hormones↗
PubMed2004

Auditory integration training and other sound therapies for autism spectrum disorders.

BACKGROUND: Autism spectrum disorders (ASD) are a heterogeneous group of disorders encompassing Autistic Disorder, Asperger's Disorder, Semantic-Pragmatic disorder and Pervasive Developmental Disorder Not Otherwise Specified. Auditory integration therapy (AIT) was developed as a technique for improving abnormal sound sensitivity in individuals with behavioural disorders including autism. Other sound therapies bearing similarities to AIT include the Tomatis Method and Samonas Sound Therapy. OBJECTIVES: To determine the effectiveness of AIT or other methods of sound therapy in individuals with ASD. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2003), MEDLINE (1966 - February 2002), EMBASE (1980 - February 2002), CINAHL (1982 - December 2001), PsycINFO (1887 - February 2002), ERIC (1965 - December 2001) and LILACS (1982 - March 2002). Reference lists of articles identified electronically were searched for further relevant publications. SELECTION CRITERIA: Randomised controlled trials of adults or children with ASD. Treatment was auditory integration therapy (AIT) or other sound therapies involving listening to music modified by filtering and modulation. Control groups could be no treatment, waiting list, usual therapy or placebo equivalent. Outcomes sought were changes in core and associated features of ASD, auditory processing, quality of life and adverse events. DATA COLLECTION AND ANALYSIS: All outcome data reported in included papers were continuous. Initial intention was to undertake meta-analyses using mean difference and standard deviation to take into account differences between treatment and control groups at baseline. These data were not available. Instead, point estimates and standard errors were calculated from t-test scores and post intervention means. Meta-analysis was attempted but deemed inappropriate at present. MAIN RESULTS: No trials assessing sound therapies other than AIT were found. Six RCTs of AIT, including one cross-over trial, were identified with a total of 171 individuals aged 3-39 years. Four trials had fewer than 20 participants. Allocation concealment was inadequate for all of the studies. Seventeen different outcome measures were used. Only two outcomes were used by three or more studies: Aberrant Behaviour Checklist (ABC) (5) and Fisher's Auditory Problems Checklist (FAPC) (3). Meta-analysis was not possible due to very high heterogeneity (Aberrant Behaviour Checklist subscores), or presentation of data in unusable forms. Three studies (Bettison 1996, Zollweg 1997, Mudford 2000) did not demonstrate benefit of AIT over control conditions. The remaining trials (Veale 1993, Rimland 1995, Edelson 1999) reported improvements at 3 months for the AIT group based on improvements of total mean scores for the ABC, which is of questionable validity. Rimland 1995 also reported improvements at 3 months in the AIT group for ABC subgroup scores. No significant adverse effects of AIT were reported. REVIEWER'S CONCLUSIONS: More research is needed to inform parents', carers' and practitioners' decision making about this therapy for individuals with autism spectrum disorders.

Acoustic Stimulation↗
PubMed2006

Routine surgery in addition to chemotherapy for treating spinal tuberculosis.

BACKGROUND: Tuberculosis is generally curable with chemotherapy, but there is controversy in the literature about the need for surgical intervention in the one to two per cent of people with tuberculosis of the spine. OBJECTIVES: To compare chemotherapy plus surgery with chemotherapy alone for treating people diagnosed with active tuberculosis of the spine. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (October 2005), CENTRAL (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to October 2005), EMBASE (1974 to October 2005), LILACS (1982 to October 2005), conference proceedings, and reference lists. SELECTION CRITERIA: Randomized controlled trials with at least one year follow up that compared chemotherapy plus surgery with chemotherapy alone for treating active tuberculosis of the thoracic and/or lumbar spine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, methodological quality, and extracted data. We analysed data using odds ratio with 95% confidence intervals. MAIN RESULTS: Two randomized controlled trials (331 participants) met the inclusion criteria. They were conducted in the 1970s and 1980s with follow-up reports available after 18 months, three years, and five years; one trial also reported 10 years follow up. Completeness of follow up varied at the different time points, with less than 80% of participants available for analysis at several time points. There was no statistically significant difference for any of the outcome measures: kyphosis angle, neurological deficit (none went on to develop this), bony fusion, absence of spinal tuberculosis, death from any cause, activity level regained, change of allocated treatment, or bone loss. Neither trial reported on pain. Of the 130 participants allocated to chemotherapy only, 12 had a neurological deficit and five needed a decompression operation. One trial suggested that an initial kyphosis angle greater than 30 degrees is likely to deteriorate, especially in children. AUTHORS' CONCLUSIONS: The two included trials had too few participants to be able to say whether routine surgery might help. Although current medication and operative techniques are now far more advanced, these results indicate that routine surgery cannot be recommended unless within the context of a large, well-conducted randomized controlled trial. Clinicians may judge that surgery may be clinically indicated in some groups of patients. Future studies need to address these topics as well as the patient's view of their disease and treatment.

Aminosalicylic Acid↗
PubMed2002

Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants.

Excitotoxicity has been implicated in the etiology of ischemic stroke and chronic neurodegenerative disorders. Hence, the development of novel neuroprotectant molecules that ameliorate excitotoxic brain damage is vigorously pursued. We used a neuroprotection-based cellular assay to screen a synthetic combinatorial library of N-alkylglycine trimers. Two compounds (6-1-2 and 6-1-10) that efficiently prevented excitotoxic neurodegeneration in vitro and in vivo were identified. Both molecules protected primary cultures of cerebellar neurons against glutamate-induced neuronal death with an efficiency equivalent to N-methyl-D-aspartate (NMDA) receptor antagonists. These trialkylglycines did not block appreciably the NMDA receptor channel, or attenuated glutamate-induced increase of Ca(2+), or affect the glutamate-nitric oxide-cGMP pathway. Intraperitoneal injection of both peptoids in mice attenuated > or = 80% ammonia-induced, NMDA receptor-mediated animal death. Furthermore, these two molecules reduced by > or = 50% the neurodegeneration in striatum in a rat model of cerebral ischemia. Neuroprotection against ischemia was associated with decreased activation of caspase-3, reflecting prevention of apoptotic neuronal death. Collectively, the results reported indicate that these trialkylglycines are new neuroprotectant leads with important in vivo activity against excitotoxicity, and that they act on a novel, yet-unrecognized cellular target. These lead compounds may become tolerated drugs for the treatment of acute and chronic neurodegenerative diseases with fewer side effects than NMDA receptor antagonists.

Ammonia↗
PubMed1997

Molecular cloning of a ripening-specific lipoxygenase and its expression during wild-type and mutant tomato fruit development.

A 94-kD protein that accumulates predominately in tomato (Ly-copersicon esculentum) fruit during ripening was purified, and antibodies specific for the purified protein were used to isolate cDNA clones from a red-ripe fruit cDNA library. A sequence analysis of these cDNAs and cross-reactivity of the 94-kD-specific antibodies to the soybean lipoxygenase (LOX) L-1, L-2, and L-3 proteins and soybean LOX L-1-specific antibodies to the 94-kD protein identified it as a member of the LOX gene family. Maximum levels of the 94-kD LOX mRNA and protein are present in breaker to ripe and red-ripe stages, respectively. Expression of 94-kD LOX in different tissues from mature green and red-ripe tomato fruits was found to be greatest in the radial walls of ripe fruit, but immunocytolocalization using tissue printing suggests that the highest accumulation of its protein occurs in locular jelly. None of 94-kD LOX is expressed in nonripening mutant fruits of any age. Never-ripe mutant fruit accumulate the 94-kD LOX mRNA to levels similar to those obtained in wild-type fruit, but fail to accumulate the 94-kD LOX protein. Collectively, the results show that expression of 94-kD LOX is regulated by the ripening process, and ethylene may play a role in its protein accumulation.

Cloning, Molecular↗
PubMed2003

Supplemental oxygen for the treatment of prethreshold retinopathy of prematurity.

BACKGROUND: Oxygen has long been implicated in the pathogenesis of retinopathy of prematurity (ROP) and is rigorously monitored in today's neonatal intensive care units. Recent research using a feline model has shown an improvement in ROP outcome of kittens treated with supplemental oxygen. Current treatment for ROP by retinal ablation is not without complications so a non-invasive method of treatment is preferred. The possible effects of long term oxygen supplementation on chronic lung disease, length of hospital stay and growth and development are, however, unknown. OBJECTIVES: To determine whether, in preterm or low birth weight infants with prethreshold ROP, targeting higher as compared to normal transcutaneous oxygen levels or pulse oximetry levels when using supplemental oxygen reduces the progression of ROP to threshold disease and improves visual outcome without any adverse effects. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, MEDLINE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants and journal handsearching. An additional literature search of the MEDLINE (1966-June 2002), EMBASE (1980-April 2002), and CINAHL (1982-April 2002) databases was conducted in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR, The Cochrane Library Issue 2, 2002). SELECTION CRITERIA: All randomised or quasi randomised studies comparing higher versus normal target oxygen levels in preterm or low birthweight infants with prethreshold ROP were eligible for inclusion. DATA COLLECTION AND ANALYSIS: The methodological quality of the one eligible trial was assessed independently by two authors for the degree of selection, performance, attrition and detection bias. Data regarding clinical outcomes including progression to threshold ROP, blindness or severe visual impairment, mortality, respiratory morbidities and long term growth were extracted and reviewed independently by two authors. Results were compared and differences resolved as required. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: The one trial included in this review enrolled 649 infants. There was a trend for supplemental oxygen to reduce the progression to threshold ROP, however this did not reach statistical significance (RR 0.84, 95% CI 0.70, 1.02). A subgroup analysis of those infants without plus disease showed significantly fewer infants progressing to threshold ROP in infants treated with supplemental oxygen. However this analysis was not pre-specified so these results should be interpreted with caution. No significant effects were detected on blindness or severe visual function at three months corrected age, mortality, pneumonia, chronic lung disease or weight gain. Adverse pulmonary events were more common in the higher oxygen saturation group and these infants were in hospital and on supplemental oxygen for longer. Longer term visual outcomes were not reported. REVIEWER'S CONCLUSIONS: The results of this systematic review do not show a statistically significant reduction in the rate of progression to threshold ROP with supplemental oxygen treatment, but reveal increased adverse pulmonary sequelae with higher oxygen targeting in this group of preterm infants. Future research needs to be directed towards the question of whether infants without plus disease are more likely to respond to supplemental oxygen therapy than those with plus disease.

Humans↗
PubMed2004

Drug discovery and epithelial physiology.

PURPOSE OF REVIEW: Small-molecule inhibitors and activators of gene products or cell functions can be valuable research tools for analyzing gene function ('chemical genetics'), and as leads for the development of new therapies ('drug discovery'). The recent National Institutes of Health roadmap highlights small-molecule discovery and applications in cellular and in-vivo systems as an important new research direction. The purpose of this review is to explain the small-molecule discovery process for investigators doing research in an academic setting, with emphasis on advances and directions in epithelial transport physiology. RECENT FINDINGS: The small-molecule discovery process involves the identification and validation of gene or phenotype targets, the screening of collections of small compounds for activity against the target, and the evaluation and optimization of compounds of interest. Many potential targets in renal epithelial physiology are suitable for small-molecule identification. Although small-molecule discovery in epithelial biology is in its infancy, recent advances have been reported in modulating the function of epithelial chloride channels, including the cystic fibrosis transmembrane conductance regulator and ClC-type chloride channels. SUMMARY: Small-molecule discovery by the screening of chemical libraries is feasible in the academic setting, and holds great potential for the elucidation of gene function and complex regulatory pathways, and the identification of lead drug candidates for rare diseases and diseases of limited commercial interest. The rapid chemical turn-off of gene function addresses the concerns of compensatory/developmental changes in cell and animal models of gene deletion.

Animals↗