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PubMed2002

Antibiotic regimens for management of intraamniotic infection.

BACKGROUND: Intraamniotic infection is associated with maternal morbidity and neonatal sepsis, pneumonia and death. Although antibiotic treatment is accepted as the standard of care, few studies have been conducted to examine the effectiveness of different antibiotic regimens for this infection and whether to administer antibiotics intrapartum or postpartum. OBJECTIVES: To study the effects of different maternal antibiotic regimens for intraamniotic infection on maternal and perinatal morbidity and mortality. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (May 2002) and the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2002). SELECTION CRITERIA: Trials where there was a randomized comparison of different antibiotic regimens to treat women with a diagnosis of intraamniotic infection were included. The primary outcome was perinatal morbidity. DATA COLLECTION AND ANALYSIS: Data were extracted from each publication independently by the authors. MAIN RESULTS: Two eligible trials (181 women) were included in this review. No trials were identified that compared antibiotic treatment with no treatment. Intrapartum treatment with antibiotics for intraamniotic infection was associated with a reduction in neonatal sepsis (relative risk (RR) 0.08; 95% confidence interval (CI) 0.00, 1.44) and pneumonia (RR 0.15; CI 0.01, 2.92) compared with treatment given immediately postpartum, but these results did not reach statistical significance (number of women studied = 45). There was no difference in the incidence of maternal bacteremia (RR 2.19; CI 0.25, 19.48). There was no difference in the outcomes of neonatal sepsis (RR 2.16; CI 0.20, 23.21) or neonatal death (RR 0.72; CI 0.12, 4.16) between a regimen with and without anaerobic activity (number of women studied = 133). There was a trend towards a decrease in the incidence of post-partum endometritis in women who received treatment with ampicillin, gentamicin and clindamycin compared with ampicillin and gentamicin alone, but this did not reach statistical significance (RR 0.54; CI 0.19, 1.49). REVIEWER'S CONCLUSIONS: The conclusions that can be drawn from this meta-analysis are limited due to the small number of studies. For none of the outcomes was a statistically significant difference seen between the different interventions. Current consensus is for the intrapartum administration of antibiotics when the diagnosis of intraamniotic infection is made; however, the results of this review neither support nor refute this although there was a trend towards improved neonatal outcomes when antibiotics were administered intrapartum. No recommendations can be made on the most appropriate antimicrobial regimen to choose to treat intraamniotic infection.

Amnion↗
PubMedDate not supplied

PACS support: the radiology approach.

In 1999, Rex Healthcare, a 394-bed facility located in Raleigh, N.C., faced a growing problem. The radiology department was performing a total of 130,000 procedures a year, running out of space to store the film, and having trouble managing the file room. While the IT department was focused on the Y2K scare, radiology forged ahead with a plan to implement PACS on its own at Rex Hospital. Rex had installed a mini-PACS system for ultrasound in 1996, but there was no internal support for the system's hardware or software. Being the first in the area to implement PACS, Rex wasn't able to recruit anyone locally to support the system, so they decided to take two areas that PACS had a great impact on and use their own people. The director of radiology asked the RIS analyst and the Film Library manager, both of whom were registered technologists, to implement and support the PAC system. The key to PACS support is not computer knowledge, although it helps. The key is to understand the radiology department as a whole and the workflow from within, which makes it hard to fully support from an IT perspective. The current PACS team at Rex is composed of a PACS analyst, system support specialist and an electronic imaging center manager. When we went live with PACS, it was obvious that not all of the existing file room personnel would make the technology leap, which they realized themselves. We didn't push anybody out, but we did raise the bar of expectations. By redefining job descriptions and having the EITs (electronic imaging technologists) become more involved, increased respect was quite evident among the hospital staff. The clerks that once only hung and filed films are now troubleshooting CD burners, teaching physicians the PACS, and filming necessary exams. The final key to success is to take ownership of your system. By taking ownership, I mean that a PACS team should be established to do troubleshooting and first-line support, know the servers and application, and feel comfortable performing daily checks and tasks. Being an advanced radiology PACS site in our area, we have become an important facility for site visits. We take site visits very seriously, and have composed a package that includes information about the hospital, network/modality diagrams, EIT job descriptions, PACS information and various time studies that we have completed since going firmless. An administrator with a vision and strong support from within will get a PACS up and running, but ongoing upkeep requires a team that is dedicated to the success of the project. By taking ownership of the system and following the keys to success, a department has the ability to reengineer radiology workflow not just in the hospital, but in the community as well.

Hospital Bed Capacity, 300 to 499↗
PubMed2002

Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines.

A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC(50) of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC(50)'s of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.

ATP Binding Cassette Transporter 1↗
PubMed1997

Chasing the ambulance. The emerging crisis in the preservation of modern health records.

In this brief essay we argue that the best efforts of archivists, scholars, and practitioners within the National Health Service have not prevented the wholesale destruction of the bulk of patient records created during the twentieth century. This is a matter of vital concern not merely for historians of modern medicine. Important clinical work has frequently been undertaken on materials which have survived, usually by chance or by the foresight of physicians, matrons, and administrators. Even the significant fragments of historical documents which remain in the hands of the health authorities have been threatened by the continuing drive to reduce storage and maintenance costs within hospitals. Archivists and academics have struggled to address the problems of sampling, storage, and access which the enormous bulk of modern records present. In this essay we suggest that the first step must be to raise awareness amongst professionals and the public of the extent to which any future history of the medical services and of patient care will depend on a reasonable rate of survival of these records. The second step must be to confront the problem of resources and the inevitable task of selection which must form the foundations of any long-term policy of preservation. An initial survey of archival materials in Devon indicates that the records of community health care form a substantial and potentially invaluable research source for future historians, though their relevance has rarely been recognized within the academic community.

Archives↗
PubMed2000

Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum.

Degeneration of serotonergic fibers in the rat striatum was produced by local administration of the serotonergic neurotoxin 5, 7-dihydroxytryptamine (5,7-DHT) or the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which is also toxic to serotonergic neurons. One week before neurotoxin administration, fibroblasts engineered to express the human BDNF gene were grafted into the mesencephalon, dorsal to the substantia nigra. Rats implanted with fibroblasts expressing the LacZ gene were used as controls, as well as sham-operated animals (not injected with any neurotoxin). After a survival period of 1 week, the serotonergic innervation of the striatum was assessed by measuring serotonin (5-HT) content and by immunohistochemical detection of 5-HT positive fibers. BDNF-producing cells prevented the striatal 5-HT loss induced by local administration of either 5,7-DHT or MPP(+), as well as the striatal dopamine (DA) loss induced by the latter neurotoxin. Grafting of fibroblasts carrying the BDNF or the Lac-Z gene did not modify striatal 5-HT or DA content in sham-operated animals. In 5, 7-DHT-lesioned rats, implanted or not with control Lac-Z fibroblasts, a striking reduction in the density of 5-HT immunoreactive fibers was observed. By contrast, the density of 5-HT fibers was similar in rats implanted with BDNF-producing fibroblasts as compared to sham-operated controls. The protective effect of BDNF on the damage to serotonergic terminals induced by the two neurotoxins suggests the interest of this neurotrophin in the treatment of behavioral disorders associated to neurodegenerative diseases.

1-Methyl-4-phenylpyridinium↗
PubMed2006

Additional bedtime H2-receptor antagonist for the control of nocturnal gastric acid breakthrough: a Cochrane systematic review.

OBJECTIVES: To assess the effectiveness and safety of additional bedtime H(2)-receptor antagonists (H(2)RAs) in suppressing nocturnal gastric acid breakthrough (NAB) via a systematic review. METHODS: Eligible trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 2, 2004), MEDLINE (January 1966-June 2004), EMBASE (January 1980-June 2004) and CINAHL (January 1982-June 2004). Additional hand-searching was conducted on the proceedings of correlated conferences, eight important Chinese journals and references of all included trials. All randomized controlled trials evaluating H(2)RAs for the control of NAB were eligible for inclusion. The systematic review was conducted using methods recommended by The Cochrane Collaboration. RESULTS: Only two randomized crossover studies, comprising 32 participants, met the inclusion criteria. Because the design, dosage and duration of the treatments were different between the studies, it was not possible to conduct meta-analysis. There were no consistent conclusions found between the two included studies in evaluating H(2)RAs for the control of NAB. CONCLUSIONS: No implications for practice at this stage can be concluded. Appropriately designed large-scale randomized controlled trials with long-term follow up are needed to determine the effects of additional bedtime H(2)RAs in suppressing NAB.

Drug Administration Schedule↗
PubMed2005

Corticosteroid treatment of periorbital haemangioma of infancy: a review of the evidence.

AIM: To systematically review the literature for corticosteroid treatment of periorbital haemangioma of infancy (HOI) and determine the relative efficacy and safety of oral, topical and intralesional corticosteroids. METHODS: PubMed and the Cochrane Library were queried using keywords, and further articles were obtained by reviewing bibliographies. Inclusion and exclusion criteria were applied to create a subset of literature for analysis. RESULTS: Systematic review revealed 81 original reports of periorbital HOI cases treated with steroids. Most studies and case series failed to document refractive error or visual acuity before and after treatment. Of cases meeting inclusion criteria, five patients received topical steroids and 25 patients received intralesional steroids. Patients receiving intralesional injections tended to demonstrate reduced astigmatism at follow up after treatment (21 of 28). The lack of studies with relevant objective ophthalmological end points prevented statistical meta-analysis. CONCLUSION: Intralesional injections may reduce refractive error, while the efficacy of topical steroids is unclear. Studies measuring objective ophthalmic data before and after treatment are sparse, and more studies are needed to determine the relative efficacy of different steroids. There are insufficient data to estimate the incidence of steroid side effects in patients treated with steroids for periorbital HOI or complications of intralesional injections in particular.

Administration, Oral↗
PubMed2004

Proton pump inhibitor treatment for acute peptic ulcer bleeding.

BACKGROUND: Peptic ulcer (PU) bleeding is associated with substantial morbidity, mortality and healthcare cost. Randomised controlled trials (RCTs) evaluating the clinical effect of proton pump inhibitors (PPIs) in peptic ulcer bleeding have yielded conflicting results. OBJECTIVES: To evaluate the efficacy of PPIs in the management of acute bleeding from PU using evidence from RCTs. SEARCH STRATEGY: We performed a search of CENTRAL, The Cochrane Library (Issue 3, 2003), MEDLINE (1966 to February 2003) and EMBASE (1980 to February 2003) and proceedings of recent major meetings through to February 2003. We searched the reference lists of articles and contacted pharmaceutical companies and experts in the field for additional published or unpublished data. SELECTION CRITERIA: RCTs of PPI treatment (oral or intravenous) compared with either placebo or H(2)-receptor antagonist (H(2)RA) in patients with acute bleeding from PU were included if they met pre-defined criteria. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently on a purpose-designed data extraction form. Validity of included studies was assessed by adequacy of randomisation method and other pre-defined criteria. Studies were summarised and meta-analysis was undertaken. The influence of factors on the outcomes was assessed. MAIN RESULTS: Twenty-one RCTs with a total of 2915 participants were included. Statistical heterogeneity was found among trials for rebleeding (P = 0.05), but not for mortality (P = 0.26) or surgery (P = 0.42). There was no significant difference in mortality rates between PPI and control treatment; pooled rates were 5.2% on PPI versus 4.6% on control (odds ratio (OR) 1.11; 95% CI 0.79 to 1.57). PPI treatment significantly reduced rates of surgical intervention compared with control; pooled rates were 8.4% on PPI versus 13.0% on control (OR 0.59; 95% CI 0.46 to 0.76). PPIs significantly reduced rebleeding compared to control; pooled rates were 10.6% with PPI (range: 0% to 24.4%) versus 18.7% with control treatment (range: 2.3% to 39.1%), the OR was 0.46 (95% CI 0.33 to 0.64). Results on mortality and rebleeding rates were independent of route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. Surgical intervention rates varied with type of control (PPI significantly reduced surgical intervention rates compared with placebo and not when compared with H(2)RA) but not with route of PPI administration or application of initial endoscopic haemostatic treatment. REVIEWERS' CONCLUSIONS: PPI treatment in PU bleeding reduces rebleeding and surgical intervention rates in studies comparing treatment with placebo or H(2)RA, but there is no evidence of an effect on mortality.

Acute Disease↗
PubMed2006

Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method.

BACKGROUND: Sublingual immunotherapy (SLIT) is effective and safe in the treatment of allergic rhinitis. However, there is no meta-analysis in asthma treatment. METHODS: The clinical efficacy of SLIT for asthma was evaluated through a systematic review with meta-analysis. MEDLINE (1966-2005), EMBASE (1974-2005), LILACS (1982-2005), and the Cochrane Library were searched for related literature in any language. Randomized-controlled clinical trials (RCT) on SLIT in asthma treatment for adults and children were selected. From 119 citations, 25 studies with 1706 patients were included in this meta-analysis. For each report, quality scores were assigned and data were extracted in relation to the outcomes analyzed: asthmatic symptoms, use of asthma medications, lung function, and bronchial provocation. RESULTS: According to the Jadad quality method, 64% of the studies were assigned scores of 4 or 5. Immunotherapy was seen to significantly reduce asthma severity when parameter compositions were all analyzed by categorical outcomes. There was a nonsignificant reduction in asthma symptoms when analyzed using standardized mean differences. No severe reactions were observed. CONCLUSIONS: This meta-analysis found that SLIT is beneficial for asthma treatment albeit the magnitude of the effect is not very large. Moreover, it is a safe alternative to the subcutaneous route. More RCT with standardization of symptom scores and medications are needed in order to contribute further to this subject.

Administration, Sublingual↗
PubMed2003

Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use.

BACKGROUND: Proton pump inhibitors have a prominent role in the management of acid-related diseases. Controlling expenses on proton pump inhibitors would yield great economic benefits for Dutch health care. AIM: To investigate whether clinical differences in proton pump inhibitors exist. METHODS: We searched Medline, EMBASE and the Cochrane Library. We identified papers in English, German, French or Dutch in which two or more proton pump inhibitors were compared under the same clinical conditions in gastro-oesophageal reflux disease, peptic ulcer disease or Helicobacter pylori eradication. The pooled relative risks were calculated using the Mantel-Haenszel method. RESULTS: Two significant differences were found in the proton pump inhibitors compared. In gastro-oesophageal reflux disease, esomeprazole 40 mg was superior to omeprazole 20 mg (relative risk, 1.18; 95% confidence interval, 1.14-1.23). In peptic ulcer disease, pantoprazole 40 mg was superior to omeprazole 20 mg (relative risk, 1.07; 95% confidence interval, 1.02-1.13). In Helicobacter pylori eradication, no significant differences were found. CONCLUSIONS: Both significant differences found were in favour of the highest dose of proton pump inhibitor on a milligram basis. This indicates that the difference may be dose dependent and not proton pump inhibitor specific. Therefore, when prescribing proton pump inhibitors, arguments other than clinical efficacy, such as those related to pharmaco-economics, may be considered.

Administration, Oral↗
PubMed2006

Opioid antagonists with minimal sedation for opioid withdrawal.

BACKGROUND: Managed withdrawal is necessary prior to drug-free treatment. It may also represent the end point of long-term opioid replacement treatment. OBJECTIVES: To assess the effectiveness of opioid antagonists in combination with minimal sedation to induce withdrawal, in terms of intensity of withdrawal, adverse effects and completion of treatment. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2005, which includes the Cochrane Drugs and Alcohol Group register), MEDLINE (January 1966 to August 2005), EMBASE (January 1985 to August 2005), PsycINFO (1967 to August 2005), and CINAHL (1982 to July 2005) and reference lists of articles. SELECTION CRITERIA: Experimental interventions involved the use of opioid antagonists in combination with minimal sedation to manage withdrawal in opioid-dependent participants compared with other approaches or different opioid antagonist regime. DATA COLLECTION AND ANALYSIS: One reviewer assessed studies for inclusion and undertook data extraction and trial quality. Study authors were contacted for additional information. MAIN RESULTS: Nine studies (5 randomised controlled trials), involving 775 participants, met the inclusion criteria for the review. Withdrawal induced by opioid antagonists in combination with an adrenergic agonist is more intense than withdrawal managed with clonidine or lofexidine alone, but the overall severity is less. Limited data showed that antagonist-induced withdrawal may be more severe when the last opioid used was methadone rather than heroin or another short-acting opioid. Delirium may occur following the first dose of opioid antagonist, particularly with higher doses (> 25mg naltrexone). The studies included suggest there is no significant difference in rates of completion of treatment for withdrawal induced by opioid antagonists, in combination with an adrenergic agonist, compared with adrenergic agonist alone. AUTHORS' CONCLUSIONS: The use of opioid antagonists combined with alpha2 adrenergic agonists is a feasible approach to the management of opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist.A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium. Further research is required to confirm the relative effectiveness of antagonist-induced regimes, as well as variables influencing the severity of withdrawal, adverse effects, the most effective antagonist-based treatment regime, and approaches that might increase retention in subsequent naltrexone maintenance treatment.

Adrenergic alpha-Agonists↗
PubMed1997

[Anesthesia ventilators].

OBJECTIVE: To review anaesthesia ventilators in current use in France by categories of ventilators. DATA SOURCES: References were obtained from computerized bibliographic search. (Medline), recent review articles, the library of the service and personal files. DATA SYNTHESIS: Anaesthesia ventilators can be allocated into three groups, depending on whether they readminister expired gases or not or allow both modalities. Contemporary ventilators provide either constant volume ventilation, or constant pressure ventilation, with or without a pressure plateau. Ventilators readministering expired gases after CO2 absorption, or closed circuit ventilators, are either of a double- or a single-circuit design. Double-circuit ventilators, or pneumatical bag or bellows squeezers, or bag-in-bottle or bellows-in-bottle (or box) ventilators, consist of a primary, or driving circuit (bottle or box) and a secondary or patient circuit (including a bag or a bellows or membrane chambers). Bellows-in-bottle ventilators have either standing bellows ascending at expiration, or hanging bellows, descending at expiration. Ascending bellows require a positive pressure of about 2 cmH2O throughout exhalation to allow the bellows to refill. The expired gas volume is a valuable indicator for leak and disconnection. Descending bellows generate a slight negative pressure during exhalation. In case of leak or disconnection they aspirate ambient air and cannot act therefore as an indicator for integrity of the circuit and the patient connection. Closed circuit ventilators with a single-circuit (patient circuit) include a insufflating device consisting either in a bellows or a cylinder with a piston, operated by a electric or pneumatic motor. As the hanging bellows of the double circuit ventilators, they generate a slight negative pressure during exhalation and aspirate ambient air in case of leak or disconnection. Ventilators not designed for the readministration of expired gases, or open circuit ventilators, are generally stand-alone mechanical ventilators modified to allow the administration of inhalational anaesthetic agents.

Anesthesia, Closed-Circuit↗
PubMed2005

Antibiotics for reduction of posttonsillectomy morbidity: a meta-analysis.

OBJECTIVE: To reconcile conflicting published reports regarding the clinical efficacy of postoperative antibiotics for reduction of posttonsillectomy morbidity. STUDY DESIGN: Systematic review (meta-analysis). METHODS: Meta-analysis of seven randomized controlled trials of postoperative oral antibiotics in patients undergoing tonsillectomy or adenotonsillectomy. Postoperative pain and time to return to normal activity and diet were studied as distinct end points using a random effects model with weighted mean difference (RevMan 4.2). Search strategy included electronic searches of PubMed and Cochrane library databases; cross-referencing textbooks, reviews, and original trials; and contacting experts in the field. RESULTS: Subjects treated with antibiotics experienced an earlier return to a normal diet (-1.22 days; 95% confidence interval [CI] = -1.97, -0.48; P = .001) and an earlier return to normal activity (-0.99 days; 95% CI = -1.80, -0.17; P = .02). Evaluation of mean pain visual analogue scores (VAS 0-10) over the first 5 and 7 postoperative days failed to demonstrate any significant effect of antibiotic therapy (VAS difference over 5 days = 0.41; -1.18, 2.00; P = .61) (VAS difference over 7 days = -0.64; -3.46, 2.18; P = .66). Cost analysis suggests routine therapy may be cost-effective but did not include analysis of side effects or resistance resulting from antibiotic usage. CONCLUSION: The results of this systematic meta-analysis suggest that postoperative oral antibiotics do not significantly reduce posttonsillectomy pain but result in an earlier return to normal activity and diet by approximately 1 day. Given the frequency that tonsillectomy is performed, this possible benefit should be weighed against the cost and potential side effects of routine antibiotic therapy.

Adenoidectomy↗
PubMed2001

Tumor targeting using anti-her2 immunoliposomes.

We have generated anti-HER2 (ErbB2) immunoliposomes (ILs), consisting of long circulating liposomes linked to anti-HER2 monoclonal antibody (MAb) fragments, to provide targeted drug delivery to HER2-overexpressing cells. Immunoliposomes were constructed using a modular strategy in which components were optimized for internalization and intracellular drug delivery. Parameters included choice of antibody construct, antibody density, antibody conjugation procedure, and choice of liposome construct. Anti-HER2 immunoliposomes bound efficiently to and internalized in HER2-overexpressing cells in vitro as determined by fluorescence microscopy, electron microscopy, and quantitative analysis of fluorescent probe delivery. Delivery via ILs in HER2-overexpressing cells yielded drug uptake that was up to 700-fold greater than with non-targeted sterically stabilized liposomes. In vivo, anti-HER2 ILs showed extremely long circulation as stable constructs in normal adult rats after a single i.v. dose, with pharmacokinetics that were indistinguishable from sterically stabilized liposomes. Repeat administrations revealed no increase in clearance, further confirming that ILs retain the long circulation and non-immunogenicity of sterically stabilized liposomes. In five different HER2-overexpressing xenograft models, anti-HER2 ILs loaded with doxorubicin (dox) showed potent anticancer activity, including tumor inhibition, regressions, and cures (pathologic complete responses). ILs were significantly superior vs. all other treatment conditions tested: free dox, liposomal dox, free MAb (trastuzumab), and combinations of dox+MAb or liposomal dox+MAb. For example, ILs produced significantly superior antitumor effects vs. non-targeted liposomes (P values from <0.0001 to 0.04 in eight separate experiments). In a non-HER2-overexpressing xenograft model (MCF7), ILs and non-targeted liposomal dox produced equivalent antitumor effects. Detailed studies of tumor localization indicated a novel mechanism of drug delivery for anti-HER2 ILs. Immunotargeting did not increase tumor tissue levels of ILs vs. liposomes, as both achieved very high tumor localization (7.0-8.5% of injected dose/g tissue) in xenograft tumors. However, histologic studies using colloidal-gold labeled ILs demonstrated efficient intracellular delivery in tumor cells, while non-targeted liposomes accumulated within stroma, either extracellularly or within macrophages. In the MCF7 xenograft model lacking HER2-overexpression, no difference in tumor cell uptake was seen, with both ILs and non-targeted liposomes accumulating within stroma. Thus, anti-HER2 ILs, but not non-targeted liposomes, achieve intracellular drug delivery via receptor-mediated endocytosis, and this mechanism is associated with superior antitumor activity. Based on these results, anti-HER2 immunoliposomes have been developed toward clinical trials. Reengineering of construct design for clinical use has been achieved, including: new anti-HER2 scFv F5 generated by screening of a phage antibody library for internalizing anti-HER2 phage antibodies; modifications of the scFv expression construct to support large scale production and clinical use; and development of methods for large-scale conjugation of antibody fragments with liposomes. We developed a scalable two-step protocol for linkage of scFv to preformed and drug-loaded liposomes. Our final, optimized anti-HER2 ILs-dox construct consists of F5 conjugated to derivatized PEG-PE linker and incorporated into commercially available liposomal doxorubicin (Doxil). Finally, further studies of the mechanism of action of anti-HER2 ILs-dox suggest that this strategy may provide optimal delivery of anthracycline-based chemotherapy to HER2-overexpressing cancer cells in the clinic, while circumventing the cardiotoxicity associated with trastuzumab+anthracycline. We conclude that anti-HER2 immunoliposomes represent a promising technology for tumor-targeted drug delivery, and that this strategy may also be applicable to other receptor targets and/or using other delivered agents.

Animals↗
PubMed1999

Systematic review of N-acetylcysteine in cystic fibrosis.

A systematic review was carried out to evaluate whether the use of N-acetylcysteine to improve lung function in patients with cystic fibrosis is supported by published evidence. Medline and the Cochrane Library were searched and the reference lists of all retrieved papers and of relevant chapters of three major textbooks were scanned. Data on lung function (forced expiratory volume in one second (FEV1)) were extracted from controlled clinical trials and pooled as weighted mean differences for analysis. Twenty-three studies, mostly uncontrolled clinical observations, were retrieved. Only three randomized controlled clinical trials on nebulized N-acetylcysteine in cystic fibrosis were found, not showing any beneficial effect on lung function. Six randomized controlled clinical trials on oral N-acetylcysteine in cystic fibrosis were found, with a total number of 181 patients. There was a tendency towards a beneficial effect on lung function of oral N-acetylcysteine therapy on FEV1 but it was small (2.3%, 95% CI from (-0.3 to 4.9% of predicted) and of doubtful clinical relevance. In all studies, follow-up was 3 months or shorter. In conclusion, at present there is no evidence supporting the use of N-acetylcysteine in cystic fibrosis, although a beneficial effect with long-term use of N-acetylcysteine in cystic fibrosis cannot be excluded.

Acetylcysteine↗
PubMedDate not supplied

[Report on the surgery for epilepsy].

OBJECTIVE: We review the clinical indications and outcomes of surgical procedures in epilepsy which is resistant to medical treatment and the current situation and future possibilities of carrying out surgery for epilepsy in Spain. DEVELOPMENT: Search of the scientific literature included in the data base MEDLINE for the period 1995-1997, retrieval of reports in relation to agencies for the evaluation of health technology of the INAHTA network and the data base of the Cochrane library. The surgery of epilepsy reduces the frequency of seizures (the basic result analyzed) in all groups of patients, although in a very variable manner, depending on the clinical situation and type of operation. The results in patients with temporal lobe epilepsy and in those with localized lesions are particularly good (temporal lobe epilepsy and lesionectomy) (67-69% without seizures), with a follow up period of one to two years. It is estimated that in Spain between 75 and 300 new cases per year would benefit from surgery. The number of patients with drug-resistant epilepsy operated on in Spain is approximately 100-150 patients per year. CONCLUSIONS: Operations for epileptic syndromes, where there are surgically resectable lesions, should be justified by the gravity and impact of the disease on the psychosocial and functional development of the patient. Insufficiency resources are dedicated to the option of surgical treatment and perhaps they are also underused. These operations should be carried out in highly specialized centres, with adequate resources and an annual volume which guarantees excellence.

Brain↗
PubMedDate not supplied

[Methylphenidate in the treatment of attention-deficit/hyperactivity disorder: are we achieving an adequate clinical practice?].

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is the most frequent behavioural disorder in infancy and methylphenidate is the most widely used medication. AIM. To analyze if the use of methylphenidate allows a good clinical practice in ADHD in terms of efficacy, effectiveness, efficiency and safety. MATERIALS AND METHODS: Systematic review of the articles about therapeutic management of ADHD with methylphenidate published in secondary and primary publications and critical appraisal by means of methodology of the Evidence-Based Medicine Working Group. RESULTS: The main secondary information is found in the Cochrane Library, but we also detect relevant articles in Pubmed, mainly published in Journal of the American Academy of Child and Adolescent Psychiatry and Pediatrics. There are many randomized clinical trials with methylphenidate (immediate-release and extended-release methylphenidate) and some systematic review and/or meta-analysis, but these trials have some limitations (in relation to patients, interventions and outcomes) and publication bias. CONCLUSIONS: From the evidence-based analysis (and from the experience) we detect good scientific evidence that methylphenidate improve target outcomes in ADHD in the short and half-term in children (mainly 6-12 years). The treatment algorithm advises to start with methylphenidate (immediate or extended-release methylphenidate, in relation to cost-benefit parameters); when there is not response (between 10-30% of patients) or evidence of relevant secondary effects, we could consider the use of atomoxetine. There are many questions to solve based on better clinical trials: the efficacy and safety of methylphenidate in very young children and adolescents, long-term effects and the duration of the treatment.

Adolescent↗
PubMed2004

Thrombolysis for acute deep vein thrombosis.

BACKGROUND: Standard treatment for deep vein thrombosis (DVT) aims to reduce immediate complications. Use of thrombolysis or clot dissolving drugs could reduce the long-term complications of post-thrombotic syndrome (pain, swelling, skin discolouration, or venous ulceration) in the affected leg. OBJECTIVES: To determine the efficacy and safety of thrombolysis for DVT. SEARCH STRATEGY: Publications describing randomised controlled trials (RCTs) of thrombolysis versus anticoagulation for acute DVT were sought through electronic searches of the Cochrane Peripheral Vascular Diseases trials register (last searched April 2004) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library Issue 2, 2004). Additional trials were identified by reviewing reference lists of papers. There were no restrictions for language. SELECTION CRITERIA: RCTs examining thrombolysis versus anticoagulation for acute DVT and/or calf vein thrombosis were considered. DATA COLLECTION AND ANALYSIS: One reviewer (LIW) selected trials, extracted data and assessed study quality, with checking at all stages by the other reviewer (MPA). Where required, additional information was sought from trialists. MAIN RESULTS: Twelve studies were included. Complete clot lysis occurred significantly more often in the treatment group in early follow up, (relative risk (RR) 0.24; 95% confidence interval (CI) 0.07 to 0.82), and in late follow up, (RR 0.37; 95 % CI 0.25 to 0.54). A similar effect was also seen for any degree of improvement in venous patency. Significantly less post-thrombotic syndrome occurred in those receiving thrombolysis, (RR 0.66; 95 % CI 0.47 to 0.94). Leg ulceration was reduced although the data were limited by small numbers, (RR 0.53; 95 % CI 0.12 to 2.43). Venous function was improved at late follow up, but not significantly (RR 0.43; 95 % CI 0.06 to 3.17)Out of 668 patients, those receiving thrombolysis had significantly more bleeding complications, (RR 1.73; 95 % CI 1.04 to 2.88). Two strokes occurred in the treatment group (RR 1.70; 95 % CI 0.21 to 13.70). The incidence of bleeding appears to have reduced over time with the introduction of stricter selection criteria. There was no significant effect on mortality detected in either early or late follow up. Data on occurrence of pulmonary embolism (PE) and recurrent DVT were inconclusive. REVIEWERS' CONCLUSIONS: Thrombolysis appears to offer advantages in terms of reducing post-thrombotic syndrome and maintaining venous patency after DVT. Use of strict eligibility criteria has improved the safety and acceptability of this treatment. The optimum drug, dose and route of administration have yet to be determined.

Humans↗