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PubMed1999

Hyperthermia for treatment of rectal cancer: evaluation for induction of multidrug resistance gene (mdr1) expression.

Environmental stress factors, such as heat, may induce multidrug resistance gene (mdr1) expression, which could result in the disadvantageous multidrug resistance (MDR) phenotype. To evaluate this possibility in a clinical situation, we investigated mdr1 gene expression in patients with locally advanced rectal cancer who underwent preoperative radio-chemo-thermo-therapy (RCTT). Patients were classified into groups according to the treatment schedule of RCTT vs. radio-chemo-therapy (RCT) without hyperthermia (control group). Expression of the mdr1 gene was analyzed in tumors and normal rectal tissues prior to and post-treatment (RCTT or RCT, respectively) by means of semi-quantitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). The data were correlated with therapeutic response and survival parameters. Based on our evaluation criteria, in 2 of 19 tumors of the RCTT group, mdr1 gene expression was increased more than 2-fold; in 3 of 19 tumors of this group, however, mdr1 expression was decreased more than 2-fold. In the patient control group, levels of mdr1 gene expression were reduced in 2 of 8 tumors. Thus, hyperthermia combined with RCT (RCTT) in comparison with RCT alone does not lead to an increase in mdr1 gene expression in patients with locally advanced rectal cancer within the preoperative treatment schedule. The risk of inducing the classical multidrug resistance phenotype by hyperthermia was thus minimal in this clinical setting. Subsequent adjuvant chemotherapy should thus not be hindered.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Miscellaneous treatments for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of neuroleptic medication. This review, one in a series examining the treatment of tardive dyskinesia, will cover miscellaneous treatments not covered elsewhere. OBJECTIVES: The primary objective of this review was to determine whether the following interventions were associated with a reduction of TD in people with schizophrenia, or others chronic mental illnesses: botulin toxin, endorphin, estrogen, essential fatty acid, EX11582A, ganglioside, lithium, naloxone, periactin, phenylalanine, piracetam, stepholidine, tryptophan, neurosurgery, or ECT. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), Cochrane Schizophrenia Group's Register of trials (1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995), PsycLIT (1974-1995), and SCISEARCH (1995) were undertaken. References of all identified studies were searched for further trial citations. Principal authors of trials were contacted. SELECTION CRITERIA: The inclusion criteria for all relevant randomised studies were that they should focus on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced TD and compare the use of the interventions listed above versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Forty references describing 31 different trials were identified by the search strategy. Of 31 trials, 15 trials were excluded, six trials were included, eight awaiting assessment and a further two trials are pending (awaiting translation, unable to locate). Data were independently extracted by each reviewer and the odds ratio or the average differences were estimated. The reviewers assumed that people who dropped out had no improvement. MAIN RESULTS: Data were available about the efficacy and safety of cerultide, essential fatty acids, estrogen, lithium and insulin. There was a significant improvement in TD associated with the use of insulin compared to placebo (OR = 0.04, 95%CI 0.01-0.24). No significant differences between the other compounds and placebo were identified. REVIEWER'S CONCLUSIONS: There is no strong evidence to support the use of any of the agents included in this review, however because of the small sample sizes, all results must be considered inconclusive. The association between low dose insulin and improvement of TD requires replication.

Antipsychotic Agents↗

PubMed2000

Intravenous immunoglobulin for suspected or subsequently proven infection in neonates.

BACKGROUND: Congenital and nosocomial infections are important causes of neonatal morbidity and mortality. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until several months after birth. Administration of intravenous immunoglobulin provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemoluminescence. Theoretically infectious morbidity and morbidity could be reduced by the administration of intravenous immunoglobulin. OBJECTIVES: To assess the effectiveness of intravenous immunoglobulin (IVIG) to reduce mortality/morbidity caused by suspected infection in newborn infants. In secondary analyses to assess the effectiveness of IVIG to reduce mortality/morbidity in those neonates who entered into the studies with suspected infection and who later were confirmed as being infected. SEARCH STRATEGY: Medline, Embase, and Reference Update Databases were searched in November 1997, and the Cochrane Library in July 1998 using the following keywords: immunoglobulin and infant-newborn, and random allocation, or controlled trial, or randomized controlled trial (RCT). The reference lists of identified RCTs and meta-analyses, personal files and Science Citation Index were also searched. No language restrictions were applied. Unpublished data were requested from authors and information has been obtained from one author to date. SELECTION CRITERIA: The criteria used to select studies for inclusion were: 1) DESIGN: RCT (including quasi-randomized trials) 2) Newborn infants (< 28 days old) 3) INTERVENTION: IVIG for treatment of suspected (and in some infants subsequently proved) bacterial/fungal infection compared to placebo or no intervention. Suspected infection was defined as clinical symptoms and signs consistent with infection without isolation of causative organism. Proved infection was defined as: clinical symptoms and signs consistent with infection in association with isolation of causative organism from either blood culture, cerebrospinal fluid culture, urine culture (urine obtained by suprapubic tap) or a normally sterile site (e.g., liver, spleen, meninges, lung) at autopsy. 4) At least one of the following outcomes was reported: mortality during initial hospital stay; length of hospital stay; side effects; psychomotor development/growth at follow up. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted information for the outcomes of interest and one researcher (AO) checked for any discrepancies and pooled the results. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effects model are reported for dichotomous outcomes and weighted mean difference (WMD) for continuous data. NNT was calculated for outcomes that showed a statistically significant reduction in RD. Data from quasi-randomized trials were excluded in sensitivity analyses. MAIN RESULTS: Study quality was generally poor. Four of 7 identified studies (n = 208), reported on the outcomes of all randomized patients with clinically suspected infection. Mortality was reduced [RR 0.52 (95% CI; 0.28, 0.98), RD -0.102 (95% CI; -0.005, -0.199, NNT 10 (95% CI; 5, 200]. When, in a sensitivity analysis (n = 126), the results from a quasi-randomized trial (n = 82) were excluded, RR and RD remained similar, [RR 0.53 (95% CI; 0.25, 1.15), RD -0.106 (-0.232, 0.021)] but statistical significance was lost. Treatment with IVIG (six trials, n = 234) in cases of subsequently proved infection did not result in a statistically significant reduction in mortality [RR 0.62 (95% CI; 0.34, 1.12, RD -0.074 (95% CI; -0.163, 0. 014)]. Excluding in a sensitivity analysis (n = 199) a quasi-randomized trial (n = 35) changed the results slightly [RR 0. 68 (95% CI; 0.36, 1.29), RD -0.059 (-0.152, 0.035)]. There was no statistically significant between-study

Humans↗

PubMed2002

Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer.

BACKGROUND: Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early stage glottic cancer. Case series suggest that they confer similar survival advantage. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES: To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer SEARCH STRATEGY: Electronic search of MEDLINE (from 1966 to October 2000), EMBASE (from 1980 to October 2000), CINAHL (from 1982 to October 2000) and CancerLit (from 1963 to October 2000) databases and the Cochrane Controlled Trials Register. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing open surgery, endolaryngeal resection and/or radiotherapy DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed RCTs identified from the electronic searches for eligibility and methodological quality. All authors of the review discussed the results of these assessments. MAIN RESULTS: Only one RCT was identified which compared open surgery and radiotherapy among a substantial number of patients with early glottic laryngeal cancer. REVIEWER'S CONCLUSIONS: There is currently insufficient evidence to guide management decisions on the most effective treatment. Interpretation of the only large scale RCT comparing open surgery and radiotherapy in patients with early glottic cancer is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis. Endolaryngeal resection of early glottic tumours is becoming more common and a well designed multicentre RCT is warranted.

Carcinoma, Squamous Cell↗

PubMed2002

Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.

BACKGROUND: Buprenorphine has recently been reported to be an alternative to methadone and LAAM for maintenance treatment of opioid dependent individuals, differing results are reported concerning its relative effectiveness indicating the need for an integrative review. OBJECTIVES: To evaluate the effects of buprenorphine maintenance against placebo and methadone maintenance in retaining patients in treatment and in suppressing illicit drug use. SEARCH STRATEGY: We searched the following databases up to 2001, inclusive: Cochrane Drugs and Alcohol Review Group Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Current Contents, Psychlit, CORK [www. state.vt.su/adap/cork], Alcohol and Drug Council of Australia (ADCA) [www.adca.org.au], Australian Drug Foundation (ADF -VIC) [www.adf.org.au], Centre for Education and Information on Drugs and Alcohol (CEIDA) [www.ceida.net.au], Australian Bibliographic Network (ABN), and Library of Congress databases, available NIDA monographs and the College on Problems of Drug Dependence Inc. proceedings, the reference lists of all identified studies and published reviews and authors of identified RCT's were asked about any other published or unpublished relevant RCT. SELECTION CRITERIA: Randomised clinical trials of buprenorphine maintenance compared with either placebo or methadone maintenance for opioid dependence. DATA COLLECTION AND ANALYSIS: Reviewers evaluated the papers separately and independently, rating methodological quality of concealment of allocation; data were extracted independently for meta-analysis and double-entered. MAIN RESULTS: Thirteen studies met the inclusion criteria, all were randomised clinical trials, all but one were double-blind. The method of concealment of allocation was not clearly described in 11 of the studies, otherwise methodological quality was good. Buprenorphine given in flexible doses appeared statistically significantly less effective than methadone in retaining patient in treatment (RR= 0.82; 95% CI: 0.69-0.96). Low dose buprenorphine is not superior to low dose methadone. High dose buprenorphine does not retain more patients than low dose methadone, but may suppress heroin use better. There was no advantage for high dose buprenorphine over high dose methadone in retention (RR=0.79; 95% CI:0.62-1.01), and high dose buprenorphine was inferior in suppression of heroin use. Buprenorphine was statistically significantly superior to placebo medication in retention of patients in treatment at low doses (RR=1.24; 95% CI: 1.06-1.45), high doses (RR=1.21; 95% CI: 1.02-1.44), and very high doses (RR=1.52; 95% CI: 1.23-1.88). However, only high and very high dose buprenorphine suppressed heroin use significantly above placebo. REVIEWER'S CONCLUSIONS: Buprenorphine is an effective intervention for use in the maintenance treatment of heroin dependence, but it is not more effective than methadone at adequate dosages.

Buprenorphine↗

PubMed2001

Techniques for surgical retrieval of sperm prior to ICSI for azoospermia.

BACKGROUND: Azoospermia, the absence of sperm in ejaculated semen, is the most severe form of male factor infertility and is present in approximately 5% of all investigated infertile couples. The condition is currently classified as "obstructive" or "non-obstructive", although it is important to also consider the specific aetiology of each individual case. Some cases of obstructive azoospermia are treatable using microsurgical reconstruction of the seminal tract (for example, vasectomy reversal). Unreconstructable obstructive azoospermia and non-obstructive azoospermia have historically been relatively untreatable conditions that required the use of donor spermatozoa for fertilisation. The advent of intra-cytoplasmic sperm injection (ICSI), however, has transformed treatment of this type of severe male factor infertility. Sperm can be retrieved for ICSI from either the epididymis or the testis depending on the type of azoospermia. OBJECTIVES: To evaluate the efficacy of the various surgical retrieval techniques for men with obstructive or non obstructive azoospermia prior to ICSI. SEARCH STRATEGY: Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled trials, CCTR, MEDLINE, EMBASE, and Bio extracts were performed to identify relevant randomised controlled trials (RCTs). Attempts were also made to identify trials from the National Research Register, the Clinical Trial Register and the citation lists of review articles and included trials. The first or corresponding author of each included trial was also contacted for additional information. SELECTION CRITERIA: Trials were included if they were randomised and compared the effectiveness of sperm retrieval techniques in men with azoospermia prior to ICSI. Due to the lack of RCTs non-randomised trials, who used the participants as their own control, were also considered in the review but not included in the meta-analysis. Trials of surgically extracted sperm versus ejaculated sperm or of diagnostic biopsies with no sperm parameter information were excluded. DATA COLLECTION AND ANALYSIS: One RCT was included in this systematic review which compared micropuncture with nerve stimulation versus microsurgical epididymal sperm extraction. Pregnancy rate, sperm retrieval adequate for ICSI and fertilisation rate were primary outcomes. Another RCT comparing microsurgical epididymal sperm extraction versus testicular sperm extraction, was excluded from the meta-analysis due to poor randomisation. Seven non-randomised comparative trials were also identified and included. Main outcomes were pregnancy rate, sperm retrieval adequate for ICSI, fertilisation rate and implantation rate. Quality assessment and data extraction were performed independently by two reviewers. Meta-analysis was performed using odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Data unsuitable for meta-analysis was reported as descriptive data and was also included for discussion. MAIN RESULTS: One small RCT comparing two epididymal techniques gave limited evidence that microsurgical epididymal sperm aspiration (MESA) achieved significantly lower pregnancy (OR 0.19, 95% CI 0.04-0.83) and fertilisation rates (OR 0.16, 95% CI 0.05-0.48) than the micropuncture with perivascular nerve stimulation technique. However the small number of participants included and the questionable methodology of this RCT make it impossible to make a definitive statement about the relative merits of either treatment. REVIEWER'S CONCLUSIONS: There is insufficient evidence to recommend any specific sperm retrieval technique for azoospermic men undergoing ICSI. Further randomised trials are warranted, preferably multi-centred trials.

Epididymis↗

PubMed2005

Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis.

BACKGROUND: Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome. OBJECTIVES: To estimate the effects of benzodiazepines, alone or in combination with antipsychotics, when compared to placebo or antipsychotics, to control disturbed behaviour and reduce psychotic symptoms. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register (October 2002 and April 2005), inspected reference lists of included and excluded studies and contacted authors of relevant studies. SELECTION CRITERIA: We included all randomised clinical trials comparing benzodiazepines, alone or in combination with antipsychotics, with placebo or sole use of antipsychotics, for people with acute psychotic illnesses. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality assessed them and extracted data. For binary outcomes we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI), and weighted number needed to treat or harm (NNT/NNH) statistics. For continuous outcomes we estimated a weighted mean difference between groups. If heterogeneity was found, we used a random effects model. MAIN RESULTS: We included eleven studies with a total of 648 participants. When comparing benzodiazepines with placebo, sedation was equally prevalent (n=102, 1 RCT, RR 1.67 CI 0.4 to 6.6), however, fewer people allocated lorazepam remained excited at 24 hours (n=102, RR 0.62 CI 0.4 to 1.0, NNT 5 CI 3 to 59). The lorazepam and placebo group experienced similar non-significant, low levels of adverse effects. In the comparison of benzodiazepines versus use of antipsychotics without use of anticholinergics/antihistamines, people allocated benzodiazepines did not clearly need additional medication compared with those given antipsychotics (n=216, 2 RCTs, RR 1.28 CI 0.5 to 3.2). Numbers sedated were also equivocal between groups (n=324, 6 RCTs, RR 0.76 CI 0.5 to 1.2) as were mental state ratings. Extrapyramidal symptoms were significantly higher in the antipsychotic treatment group (n=391, 7 RCTs, RR 0.17 CI 0.1 to 0.4, NNT 6 CI 2 to 17). Two trials (total n=83) comparing lorazepam plus haloperidol with lorazepam alone found no clear difference for the need of additional medication (n=83, 2 RCTs, RR 1.02 CI 0.8 to 1.3) or 'not improved' at one hour (n=20, 1 RCT, RR 1.47 CI 0.66 to 3.25). There was no difference in the incidence of extrapyramidal symptoms (n=83, 2 RCTs, RR 1.94 CI 0.2 to 20.3). Finally when the benzodiazepine plus antipsychotic combination was compared with antipsychotics alone (2 RCTs, n=95) there was no difference between groups in the need for additional medications (n=67, 1 RCT, RR 0.95 CI 0.8 to 1.2) or for mental state measures. Extrapyramidal symptoms were significantly lower for people receiving both benzodiazepines and antipsychotics compared with those receiving antipsychotics alone (n=95, 2 RCTs, RR 0.45 CI 0.2 to 0.9, NNH 2 CI 1 to 5). There was no significant difference in the number of participants unfit for early discharge (n=28, 1 RCT, RR 0.90 CI 0.54 to 1.5). AUTHORS' CONCLUSIONS: There is insufficient data from these studies to support or refute the use of benzodiazepines with or without antipsychotics where emergency drugs are needed. The sole use of older antipsychotics unaccompanied by anticholinergic drugs may be problematic, but studies in this review are not large enough to identify any serious adverse effects of benzodiazepines such as respiratory depression. Larger, more informative studies are needed before definite conclusions can be drawn as to the efficacy of benzodiazapines.

Acute Disease↗

PubMed2005

Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses.

BACKGROUND: People presenting with agitated or violent behaviour thought to be due to severe mental illness may require urgent pharmacological tranquillisation. Several preparations of olanzapine, an antipsychotic drug, are now being used for management of such agitation. OBJECTIVES: To estimate the effects of intramuscular, oral-velotab, or standard oral olanzapine compared with other treatments for controlling aggressive behaviour or agitation thought to be due to severe mental illness. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Issue 1, 2002), The Cochrane Schizophrenia Group's Register (November 2004) and reference lists. We contacted authors of trials and the manufacturers of olanzapine. SELECTION CRITERIA: Randomised clinical trials comparing oral-velotab or intramuscular, or standard oral olanzapine to any treatment, for agitated or aggressive people with severe mental illnesses. DATA COLLECTION AND ANALYSIS: We reliably selected, quality assessed and data extracted studies. For binary outcomes we calculated a fixed effects Risk Ratio (RR) and its 95% Confidence Interval (CI) with a weighted Number Needed to Treat/Harm statistic (NNT/H). For continuous outcomes, we preferred endpoint data to change data and synthesised non-skewed data from valid scales using a weighted mean difference (WMD). MAIN RESULTS: Four trials compared olanzapine IM with IM placebo (total n=769, 217 allocated to placebo). Fewer people given olanzapine IM had 'no important response' by 2 hours compared with placebo (4 RCTs, n=769, RR 0.49 CI 0.42 to 0.59, NNT 4 CI 3 to 5) and olanzapine IM was as acceptable as placebo (2 RCTs, n=354, RR leaving the study early 0.31 CI 0.06 to 1.55). When compared with placebo, people given olanzapine IM required substantially fewer additional injections following the initial dose (4 RCTs, n=774, RR 0.48 CI 0.40 to 0.58, NNT 4 CI 4 to 5). Olanzapine IM did not seem associated with extrapyramidal effects (4 RCT, n=570, RR experiencing any adverse event requiring anticholinergic medication in first 24 hours 1.27 CI 0.49 to 3.26). Two trials compared olanzapine IM with haloperidol IM (total n=482, 166 allocated to haloperidol). Studies found no differences between olanzapine IM and haloperidol by 2 hours for the outcome of 'no important clinical response' (2 RCTs, n= 482, RR 1.00 CI 0.73 to 1.38) neither was there a difference for needing repeat IM injections (2 RCTs, n=482, RR 0.99 CI 0.71 to 1.38). More people on haloperidol experienced akathisia over the five day oral period compared with olanzapine IM (1 RCT, n=257, RR 0.51 CI 0.32 to 0.80, NNT 6 CI 5 to 15) and fewer people allocated to olanzapine IM required anticholinergic medication by 24 hours compared with those given haloperidol IM (2 RCTs, n= 432, RR 0.20 CI 0.09 to 0.44, NNT 8 CI 7 to 11). Two trials compared olanzapine IM with lorazepam IM (total n=355, 119 allocated to lorazepam). For the outcome of 'no important clinical response' , there was no difference between people given olanzapine IM and those allocated to lorazepam at 2 hours (2 RCTs, n=355, RR 92 CI 0.66 to 1.30) but fewer people allocated to olanzapine IM required additional injections by 24 hours compared with those on lorazepam IM (2 RCTs, n=355, RR 0.68 CI 0.49 to 0.95, NNT 10 CI 6 to 59). People receiving IM olanzapine were less likely to experience any treatment emergent adverse events, than those on lorazepam (1 RCT, n=150, RR at 24 hours 0.62 CI 0.43 to 0.89, NNT 5 CI 4 to 17) and over the same time period there were no clear differences in the use of anticholinergic medication between groups (1 RCT, n=150, RR 1.16 CI 0.38 to 3.58).No studies reported outcomes related to hospital and service use. Nor did any report on issues of satisfaction with care or suicide, self-harm or harm to others. No studies evaluated the oro-dispersable form of olanzapine. AUTHORS' CONCLUSIONS: Data relevant to the effects of olanzapine IM are taken from some studies that may not be considered ethical in many places, all are funded by a company with a pecuniary interest in the result. These studies often poorly report outcomes that are difficult to interpret for routine care. Other important outcomes are not recorded at all. Nevertheless, olanzapine IM probably has some value in helping manage acute aggression or agitation, especially where it is necessary to avoid some of the older, better, known treatments. Olanzapine causes fewer movement disorders than haloperidol and more than lorazepam. The value of the oro-dipersable velotab preparation is untested in trials. There is a need for well designed, conducted and reported randomised studies in this area. Such studies are possible and, we argue, should be designed with the patient groups and clinicians in mind. They should report outcomes of relevance to the management of people at this difficult point in their illness.

Aggression↗

PubMed2005

Music therapy for schizophrenia or schizophrenia-like illnesses.

BACKGROUND: Music therapy is a psychotherapeutic method that uses musical interaction as a means of communication and expression. The aim of the therapy is to help people with serious mental illness to develop relationships and to address issues they may not be able to using words alone. OBJECTIVES: To review the effects of music therapy, or music therapy added to standard care, compared to placebo, standard care or no treatment for people with serious mental illnesses such as schizophrenia. SEARCH STRATEGY: The Cochrane Schizophrenia Group's Register (July 2002) was searched. This was supplemented by hand searching of music therapy journals, manual searches of reference lists, and contacting relevant authors. SELECTION CRITERIA: All randomised controlled trials that compared music therapy with standard care or other psychosocial interventions for schizophrenia. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality assessed and data extracted. Data were excluded where more than 30% of participants in any group were lost to follow up. Non-skewed continuous endpoint data from valid scales were synthesised using a standardised mean difference (SMD). If statistical heterogeneity was found, treatment 'dosage' and treatment approach were examined as possible sources of heterogeneity. MAIN RESULTS: Four studies were included. These examined the effects of music therapy over the short to medium term (1 to 3 months), with treatment 'dosage' varying from 7 to 78 sessions. Music therapy added to standard care was superior to standard care alone for global state (medium term, 1 RCT, n = 72, RR 0.10 CI 0.03 to 0.31, NNT 2 CI 1.2 to 2.2). Continuous data suggested some positive effects on general mental state (1 RCT, n=69, SMD average endpoint PANSS -0.36 CI -0.85 to 0.12; 1 RCT, n=70, SMD average endpoint BPRS -1.25 CI -1.77 to -0.73),on negative symptoms (3 RCTs, n=180, SMD average endpoint SANS -0.86 CI -1.17 to -0.55) and social functioning (1 RCT, n=70, SMD average endpoint SDSI score -0.78 CI -1.27 to -0.28). However these latter effects were inconsistent across studies and depended on the number of music therapy sessions. All results were for the 1-3 month follow up. AUTHORS' CONCLUSIONS: Music therapy as an addition to standard care helps people with schizophrenia to improve their global state and may also improve mental state and functioning if a sufficient number of music therapy sessions are provided. Further research should address the dose-effect relationship and the long-term effects of music therapy.

Humans↗

PubMed2005

Thrombolytic agents for arterial and venous thromboses in neonates.

BACKGROUND: Clinically symptomatic thromboses are infrequent but serious complications in infants undergoing intensive care. Most are related to central vascular catheters. Symptomatic thrombosis may cause severe morbidity due to irreversible organ damage and also loss of limbs. OBJECTIVES: To assess the efficacy and safety of thrombolytic agents in neonatal arterial and venous thromboses. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to January 2004), EMBASE (January 1980 to January 2004), and CINAHL (January 1982 to January 2004). We also contacted authors of appropriate review articles. SELECTION CRITERIA: Randomised controlled trials (RCT) and quasi RCT comparing thrombolytic agents with either heparin or observation in neonates with symptomatic neonatal arterial and venous thromboses were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched for eligible trials. No eligible studies were found even after contacting authors of review articles for details of any unpublished trials. MAIN RESULTS: No randomised controlled trials (RCT) or quasi-RCT were found. AUTHORS' CONCLUSIONS: No conclusions could be made as no eligible studies were found. It is time that a randomised controlled trial was performed comparing thrombolytic therapy to heparin therapy to aid neonatologists in the treatment of arterial and venous thromboses.

Arteries↗

PubMed2006

Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates.

BACKGROUND: L-cysteine is thought to be a conditionally essential (i.e., essential under certain conditions) amino acid for neonates. It is a precursor of glutathione, an antioxidant that may reduce oxidation injury. The addition of cysteine to parenteral nutrition (PN) allows for the reduction of the amount of methionine in PN, thereby limiting hepatotoxicity, and acidifies the solution, thereby increasing calcium and phosphate solubility, and potentially improving bone mineralization. OBJECTIVES: To determine the effects of supplementing parenteral nutrition with cysteine, cystine or its precursor N-acetylcysteine on neonatal growth and short and long-term outcomes. SEARCH STRATEGY: The standard search method of the Cochrane Neonatal Review Group was used. MEDLINE (1966-December 2005), EMBASE (1974-December 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) and recent abstracts (until December 2005) from the Society for Pediatric Research/American Pediatric Society, Eastern Society for Pediatric Research, and Society for Parenteral and Enteral Nutrition were searched. SELECTION CRITERIA: All randomized (RCTs) and quasi-randomized trials that examined the effects of cysteine, cystine or N-acetylcysteine supplementation of neonatal PN were reviewed. Predetermined outcome variables included growth, nitrogen retention, mortality, morbidity secondary to oxidation injury, bone accretion, acidosis, liver disease, and cysteine levels. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Statistical analysis included relative risk, risk difference, and weighted mean difference (WMD). MAIN RESULTS: Six trials fulfilled entry criteria. The majority of patients in these trials were preterm. Five small trials evaluated short-term cysteine supplementation of cysteine-free PN. One large multicenter RCT evaluated short-term N-acetylcysteine supplementation of cysteine-containing PN in extremely low birth weight infants (< or = 1000 grams). PRIMARY OUTCOMES: Growth was not significantly affected by cysteine supplementation (evaluated in one quasi-randomized trial) or by N-acetylcysteine supplementation (evaluated in one RCT). Nitrogen retention was significantly increased by cysteine supplementation (studied in four trials) (WMD 31.8 mg/kg/day, 95% confidence interval +8.2, +55.4, n = 95, including 73 preterm infants). SECONDARY OUTCOMES: Plasma levels of cysteine were significantly increased by cysteine supplementation but not by N-acetylcysteine supplementation. N-acetylcysteine supplementation did not significantly affect the risks of death by 36 postmenstrual weeks, bronchopulmonary dysplasia (BPD), death or BPD, retinopathy of prematurity (ROP), severe ROP, necrotizing enterocolitis requiring surgery, periventricular leukomalacia, intraventricular hemorrhage (IVH), or severe IVH. No data were available on other outcomes. AUTHORS' CONCLUSIONS: Available evidence from RCTs shows that routine short-term cysteine chloride supplementation of cysteine-free PN in preterm infants improves nitrogen balance.However, there is insufficient evidence to assess the risks of cysteine supplementation, especially regarding metabolic acidosis, which has been reported during the first two weeks of cysteine chloride administration. Available evidence from a large RCT trial does not support routine N-acetylcysteine supplementation of cysteine-containing PN in extremely low birth weight infants. A large RCT would be required to assess whether routine prolonged cysteine supplementation of cysteine-free PN affects growth and short and long-term neonatal outcomes in very low birth weight infants.

Acetylcysteine↗

PubMed2006

Pharmacological interventions for people with borderline personality disorder.

BACKGROUND: Borderline Personality Disorder (BPD) is prevalent (2% in the general population, 20% among psychiatry in-patients) and has a major impact on health facilities as those affected often present in crisis but then make poor use of further attempts to help them. OBJECTIVES: To evaluate the effects of pharmacological interventions for people with borderline personality disorder. SEARCH STRATEGY: We conducted a systematic search of 26 specialist and general bibliographic databases (October 2002) and searched relevant reference lists for further trials. SELECTION CRITERIA: We included all randomised clinical trials comparing any psychoactive drugs with any other treatment for people with borderline personality disorder. DATA COLLECTION AND ANALYSIS: We independently selected, quality assessed and data extracted studies. For binary outcomes we calculated a standard estimation of the risk ratio (RR), its 95% confidence interval (CI), and where possible the number need to help/harm (NNT/H). For continuous outcomes, endpoint data were preferred to change data. Non-skewed data from valid scales were synthesised using a weighted mean difference (WMD). MAIN RESULTS: We found ten small (total n=554), short, randomised studies involving eight comparisons from which we could extract usable data. Studies comparing antidepressants with placebo were small (total n=79, 2 RCTs) but for ratings of anger fluoxetine may offer some improvement for those on antidepressant therapy over placebo (n=22, 1 RCT, RR anger not improved 0.30 CI 0.10 to 0.85, NNT 2 CI 2 to 9). The one small study investigating the important outcome of attempted suicide found no difference between mianserin and placebo (n=38, 1 RCT, RR 0.82 CI 0.44 to 1.54). Haloperidol may be better than antidepressants for symptoms of hostility and psychotism. There were few differences between MAOIs and placebo except that people given MAOIs were less hostile (n=62, 1 RCT, MD -9.19 CI -16.12 to -2.26). Although some ratings were statistically significant the comparison of MAOIs with antipsychotics did not show convincing differences. Antipsychotics may effect some mental state symptoms more effectively than placebo but results are difficult to interpret clinically and there is little evidence of advantage of one antipsychotic over another. Finally mood stabilisers such as divalporex may help mental state (n=16, 1 RCT, RR no improvement in mental state 0.58 CI 0.36 to 0.94, NNT 3 CI 2 to 17) but data are far from conclusive. AUTHORS' CONCLUSIONS: Pharmacological treatment of people with BPD is not based on good evidence from trials and it is arguable that future use of medication should be from within randomised trials. Current trials suggest that the positive effect of antidepressants, in particular, could be considerable. Well designed, conducted and reported clinically meaningful trials are possible and needed with, perhaps, the question of antidepressant versus placebo being addressed first.

Antidepressive Agents↗

PubMed1995

Intranasal immunization with liposomes induces strong mucosal immune responses in mice.

BALB/c mice were immunized intranasally with either soluble ovalbumin (OVA) or OVA entrapped in liposomes. The effect of adding Sigma cholera toxin B subunit (sCT-B), which contained low amounts of cholera holotoxin (CT), or recombinant CT-B (rCT-B) which was free from CT, as mucosal adjuvants was also investigated. The mucosal [lung enzyme-linked immunospot assay (ELISPOT), lung washing] and systemic (serum antibody and spleen ELISPOT) responses of immunized mice to OVA and CT-B were determined. Results showed that soluble OVA and liposome-entrapped OVA were poor inducers of mucosal or systemic responses unless CT-B was added as adjuvant. The types of responses augmented by sCT-B and rCT-B were different. CT-B containing low levels of CT (i.e. sCT-B) boosted both mucosal and systemic IgA and IgG responses, whereas rCT-B only increased IgG responses, unless antigen was entrapped in liposomes. Although rCT-B was unable to adjuvant IgA responses against soluble OVA, it was able to induce IgA responses against itself. These data show that mucosal responses can be increased by addition of CT-B containing low levels of CT to antigen preparations given intranasally, suggesting a direct role for CT-A in isotype switching. Furthermore, the ability of CT-B to adjuvant IgA responses against added antigens and its ability to induce responses against itself appear to be separate phenomena. The results from this study should assist the rational formulation of mucosal vaccines which induce potent mucosal and systemic immune responses.

Administration, Intranasal↗

PubMed2004

Neoadjuvant radiochemotherapy of oral cavity and oropharyngeal cancer: evaluation of tumor response by CT differs from histopathologic response assessment in a significant fraction of patients.

BACKGROUND: Our aim was to compare and assess the predictive value of CT and histopathologic grading of tumor regression at primary tumor sites in patients with squamous cell carcinoma of the oral cavity and oropharynx after neoadjuvant (preoperative) radiochemotherapy (RCT). METHODS: We investigated 55 patients with carcinomas of the oral cavity and oropharynx who underwent RCT before curative surgery. Two blinded observers measured RCT-induced reduction of tumor volume in pretherapeutic and posttherapeutic CT scans. Volume changes were compared with histopathologic findings obtained at surgery. RESULTS: Histopathologic response evaluation revealed 31 complete remissions, 12 cases of partial response, and 12 nonresponders. We performed a logistic regression analysis to evaluate whether measured volume reduction could predict the likelihood of belonging to a certain response group. Taken together, we found 35 correct, 12 false-negative, and seven false-positive predictions. CONCLUSIONS: The extent of remission as assessed by CT scans 4 to 5 weeks after completion of neoadjuvant RCT leads to false predictions in a significant percentage of patients.

Adult↗

PubMed2001

Healing of experimental colonic anastomoses: effects of combined preoperative high-dose radiotherapy and intraperitoneal 5-fluorouracil.

To study the effects of preoperative radiochemotherapy (RCT) on the healing of colonic anastomosis, the rectosigmoid colon in male Wistar rats was irradiated up to an end dose of 41.6 Gy (RT) or sham-irradiated (SR). During the last 5 days of the irradiation schedule, 5-fluorouracil (5-FU) was administered intraperitoneally in either a high dose (20 mg/kg, chemotherapy-high dose [CH]) or a low dose (10 mg/kg, chemotherapy-low dose [CL]). Animals were randomly arranged into six groups: group I, control (SR + saline intraperitoneally); group II, RT only; group III, SR + CL; group IV, RT + CL; group V, SR + CH; group VI, RT + CH. Four days after RCT, a side-to-side anastomosis was constructed between the irradiated rectosigmoid and the nonirradiated caecum. Animals were killed 10 days postoperatively. No significant differences were found in the anastomotic bursting pressure or the bursting wall tension. In group VI, mitoses were less (P < 0.01) and mucosal ulceration was more (P = 0.03) pronounced compared to group I. Sclerotic arteries were seen in all irradiated groups and in animals that received high-dose 5-FU alone. 5-FU administration in high or low dose, with or without RT, induced more inflammation in the submucosa compared to controls (P < 0.05). Conclusively, RCT has no detrimental effect on the mechanical strength of colonic anastomosis in this rat model. However, RCT with high-dose 5-FU induces more histological alterations at the anastomotic site.

Anastomosis, Surgical↗

PubMed2003

Increased in situ gelatinolytic activity in renal cell tumor tissues correlates with tumor size, grade and vessel invasion.

Degradation of collagen, or gelatinolysis, by tumor cells is one of the most important events in tumorigenesis. We investigate the possible relationship between the in situ gelatinolytic activities exerted by matrix metalloproteinases (MMPs) and clinico-pathological factors in renal cell tumor (RCT) patients. Using the film in situ zymography (FIZ) method, we determined in situ localization of MMP-like gelatinolytic activities in cancerous and normal tissues in the kidney (n = 51). To clarify the MMP(s) responsible for the gelatinolytic activity in RCTs, we examined the expressions of MMP-2 and MMP-9 in the kidney tissues by means of gelatin zymography (GZG). MMP expression was also detected by RT-PCR and Western blotting analysis. We then investigated the associations of MMP expression, as detected by GZG, with the intensity of gelatinolytic activity, as determined by FIZ. We analyzed the possible relationship of FIZ findings to several clinico-pathological factors such as tumor size, grade, vessel invasion, histologic type, stage and metastasis. FIZ demonstrated that all tumor and normal kidney tissues showed in situ gelatinase activities, and that gelatinolytic activities in RCTs were much stronger than those of normal kidney tissues. There was a statistically significant correlation between the intensity of MMP-like gelatinolytic activity and tumor size, tumor grade and vessel invasion (p < 0.05), but not between it and histological type, tumor stage or metastatic status. FIZ showed that tumor tissues in 5 of the 6 patients with fatal outcome exhibited the intense gelatinolytic pattern. Stronger in situ gelatinolytic patterns were documented in cases with higher MMP-2 expression. The molecular species of MMPs detected by GZG were confirmed by RT-PCR and Western blotting analysis. The FIZ technique enables a direct assessment of in situ gelatinolytic activity in RCT tissues. The intensity of the activity seems to affect the biology of RCT tissues. Our results also indicate a major role for MMP-2 in in situ gelatinolysis in RCT tissues.

Adenocarcinoma↗

PubMed2002

Clinical trials in the new millennium.

Since the introduction of the randomized clinical trial (RCT) over 50 years ago, this method has become the corner stone for evaluating new pharmacologic or biologic agents with many disease areas benefiting. There are numerous examples demonstrating beneficial interventions as well as others either not beneficial or harmful. Statistical methodology for clinical trials has grown rapidly. Advances in information technology for data collection have allowed trials to be conducted around the world. Academia, industry and government have worked in partnership to conduct RCTs. Despite these many RCT achievements, the most interesting and challenging era of clinical trials lies ahead of us. With the human genome now sequenced, we face a new set of challenges to transform vast amounts of data into useful information. The post-genomics era will better identify the disease mechanism and thus help design better treatments, and be more selective in screening patients, yielding more efficient clinical trials. For some areas of medicine, such as medical devices, standards of acceptance and regulatory approval are changing. Other areas, such as medical procedures and alternative medicines, are generally not well evaluated and could benefit greatly from a wider use of RCT methodology. As the ICH guidelines facilitate and encourage international clinical trials, the scientific and ethical dimension of conducting trials in Third World countries are raised. For example, Western society's best standard of care may not be available or affordable to these countries as the control Western investigators should not exploit patients in the Third World. Those and many other challenges face us in the decade ahead. It is truly an exciting time with new opportunities for the RCT to contribute to medicine and health care or prevention.

Data Interpretation, Statistical↗

PubMed1994

Recombinant cholera toxin B subunit in Escherichia coli: high-level secretion, purification, and characterization.

The gene coding for cholera toxin subunit B (CT-B) was fused to a modified ompA signal sequence and subsequently cloned into a high expression vector based on the regulatory signals of the arabinose operon of Salmonella typhimurium. Upon induction of gene expression in Escherichia coli, a product of the expected size for CT-B monomer was detected at a level of approximately 60% of total periplasmic protein. At pilot scale, batch cultivation in a 20-liter bioreactor allowed a production level of 1 g/liter of recombinant CT-B (rCT-B), the majority of which was released into the culture medium. The latter phenomenon was dependent on the medium selected for cultivation. A simple and inexpensive purification scheme was developed which enabled the recovery of 81% of rCT-B from the culture supernatant. Comparing amino acid composition, amino-terminal sequence, mass spectrum, pentamerisation, and GM1-binding, rCT-B is indistinguishable from natural CT-B produced by Vibrio cholerae. This rCT-B overproducing E. coli strain represents an interesting alternative to overexpressing systems developed in V. cholerae.

Amino Acid Sequence↗