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PubMed2003

[Researching documents on the history of hansen's disease in Brazil].

This article corresponds to part of the results of a research on leprosy-related sources developed in several institutions in the city of Rio de Janeiro. At Real Gabinete Português de Leitura, Arquivo Nacional and Biblioteca Nacional, banks, indexes, official documents and photos on the administration of leprosaria and articles on the treatment of the disease have been investigated. At Centro de Pesquisa e Documentação de História Contemporânea do Brazil (CPDOC-FGV), several files have been researched, mainly those with information on the health policies of the first Vargas administration (1930-1945). This research is part of the International Leprosy Association Global Project on the History of Leprosy. Its results can be accessed at the site http://www.leprosyhistory.org

Archives↗
PubMed2004

Antibiotic prophylaxis for operative vaginal delivery.

BACKGROUND: Vacuum and forceps assisted vaginal deliveries are reported to increase the incidence of postpartum infections and maternal readmission to hospital compared to spontaneous vaginal delivery. Prophylactic antibiotics are prescribed to prevent these infections. However, the benefit of antibiotic prophylaxis for operative vaginal deliveries is still unclear. OBJECTIVES: To assess the effectiveness and safety of antibiotic prophylaxis in reducing infectious puerperal morbidities in women undergoing operative vaginal deliveries including vacuum and/or forceps deliveries. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (November 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003) and MEDLINE (1966 to November 2003). SELECTION CRITERIA: All randomised trials comparing any prophylactic antibiotic regimens with placebo or no treatment in women undergoing vacuum or forceps deliveries were eligible. Participants were all pregnant women without evidence of infections or other indications for antibiotics of any gestational age undergoing vacuum or forceps delivery for any indications. Interventions were any antibiotic prophylaxis (any dosage regimen, any route of administration or at any time during delivery or the puerperium) compared with either placebo or no treatment. DATA COLLECTION AND ANALYSIS: Four reviewers assessed trial eligibility and methodological quality. Two reviewers extracted the data independently using prepared data extraction forms. Any discrepancies were resolved by discussion and a consensus reached through discussion with all reviewers. We assessed methodological quality of the included trial using the standard Cochrane criteria and the CONSORT statement of randomised controlled trials. We calculated the relative risks using a fixed effect model and all the reviewers interpreted and discussed the results. MAIN RESULTS: One trial, involving 393 women undergoing either vacuum or forceps deliveries, was included. This trial identified only two out of the nine outcomes specified in this review. It reported seven women with endomyometritis in the group given no antibiotic and none in prophylactic antibiotic group. This difference did not reach statistical significance, but the relative risk reduction was 93% (relative risks 0.07; 95% confidence interval (CI) 0.00 to 1.21). There was no difference in the length of hospital stay between the two groups (weighted mean difference 0.09 days; 95% CI -0.23 to 0.41). REVIEWERS' CONCLUSIONS: The data were too few and of insufficient quality to make any recommendations for practice. Future research on antibiotic prophylaxis for operative vaginal delivery is needed to conclude whether it is useful for reducing postpartum morbidity.

Antibiotic Prophylaxis↗
PubMed2006

Photorefractive keratectomy (PRK) versus laser-assisted in-situ keratomileusis (LASIK) for myopia.

BACKGROUND: Myopia (also known as short-sightedness or near-sightedness) is an ocular condition in which the refractive power of the eye is greater than is required, resulting in light from distant objects being focused in front of the retina instead of directly on it. The two most commonly used surgical techniques to permanently correct myopia are photorefractive keratectomy (PRK) and laser-assisted in-situ keratomileusis (LASIK). OBJECTIVES: The aim of this review was to compare the effectiveness and safety of PRK and LASIK for correction of myopia. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2005, Issue 3), MEDLINE (1966 to September 2005), EMBASE (1980 to September 2005) and LILACs (1982 to 3 November 2005). We also searched the reference lists of the studies and the Science Citation Index. SELECTION CRITERIA: We included randomised controlled trials comparing PRK and LASIK for correction of any degree of myopia. We also included data on adverse events from prospective multicentre consecutive case series in the Food and Drugs Administration (FDA) trials database (http//www.fda.gov/cdrh/LASIK/lasers.htm). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Data were summarised using odds ratio and mean difference. Odds ratios were combined using a random-effects model after testing for heterogeneity. MAIN RESULTS: This review included six randomised controlled trials involving a total of 417 eyes, of which 201 were treated with PRK and 216 with LASIK. We found that although LASIK gives a faster visual recovery than PRK, the effectiveness of these two procedures is comparable. We found some evidence that LASIK may be less likely than PRK to result in loss of best spectacle-corrected visual acuity. AUTHORS' CONCLUSIONS: LASIK gives a faster visual recovery than PRK but the effectiveness of these two procedures is comparable. Further trials using contemporary techniques are required to determine whether LASIK and PRK are equally safe.

Humans↗
PubMed1998

Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore.

A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro-2,2, 4-trimethyl-6-phenylquinoline) was discovered via directed high throughput screening of a defined chemical library utilizing an hPR-B cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl group afforded substantial improvements in hPR modulatory activity. Several analogues were able to potently block the effects of progesterone in vitro. Two compounds, 10 (LG120753) and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral administration to rodents. This is the first disclosure of orally active nonsteroidal antiprogestins.

Administration, Oral↗
PubMed2005

A peptide mimotope of type 8 pneumococcal capsular polysaccharide induces a protective immune response in mice.

Increasing antibiotic resistance and a rising patient population at risk for infection due to impaired immunity underscore the importance of vaccination against pneumococci. However, available capsular polysaccharide vaccines are often poorly immunogenic in patients at risk for pneumococcal disease. The goal of this study was to explore the potential of peptide mimotopes to function as alternative vaccine antigens to elicit a type-specific antibody response to pneumococci. We used a human monoclonal immunoglobulin A (IgA) antibody (NAD) to type 8 Streptococcus pneumoniae capsular polysaccharide (type 8 PS) to screen a phage display library, and the phage PUB1 displaying the peptide FHLPYNHNWFAL was selected after three rounds of biopanning. Inhibition studies with phage-displayed peptide or the peptide PUB1 and type 8 PS showed that PUB1 is a mimetic of type 8 PS. PUB1 conjugated to tetanus toxoid (PUB1-TT) induced a type 8 PS-specific antibody response in BALB/c mice, further defining it as a mimotope of type 8 PS. The administration of immune sera obtained from PUB1-TT-immunized mice earlier (days 14 and 21) and later (days 87 and 100) after primary and reimmunization resulted in a highly significant prolongation of the survival of naive mice after pneumococcal challenge compared to controls. The survival of PUB1-TT-immunized mice was also prolonged after pneumococcal challenge nearly 4 months after primary immunization. The efficacy of PUB1-TT-induced immune sera provides proof of principle that a mimotope-induced antibody response can protect against pneumococci and suggests that peptide mimotopes selected by type-specific human antibodies could hold promise as immunogens for pneumococci.

Animals↗
PubMed2006

Specific and sensitive analysis of nefopam and its main metabolite desmethyl-nefopam in human plasma by liquid chromatography-ion trap tandem mass spectrometry.

A specific and sensitive liquid chromatography-tandem mass spectrometric (LC-MS-MS) method using an ion trap spectrometer was developed for quantitation of nefopam and desmethyl-nefopam in human plasma. Nefopam, desmethyl-nefopam and the internal standard (ethyl loflazepate) were extracted in a single step with diethyl ether from 1 mL of alkalinized plasma. The mobile phase consisted of acetonitrile with 0.1% formic acid (50:50, v:v). It was delivered at a flow-rate of 0.3 mL/min. The effluent was monitored by MS-MS in positive-ion mode. Ionisation was performed using an electrospray ion source operating at 200 degrees C. Nefopam and desmethyl-nefopam were identified and quantified in full scan MS-MS mode using a homemade MS-MS library. Calibration curves were linear over the concentration range of 0.78-100 ng/mL with determination coefficients >0.996. This method was fast (total run time<6 min), accurate (bias<12.5%), and reproducible (intra- and inter-assay precision<17.5%) with a quantitation limit of 0.78 ng/mL. The high specificity and sensitivity achieved by this method allowed the determination of nefopam and desmethyl-nefopam plasma levels in patients following either intermittent or continuous intravenous administration of nefopam.

Calibration↗
PubMed1998

A monoclonal antibody generated by antigen inoculation via tick bite is reactive to the Borrelia burgdorferi Rev protein, a member of the 2.9 gene family locus.

Murine monoclonal antibodies directed against proteins of Borrelia burgdorferi B31 (low passage) were generated by the administration of antigen via the bite of borrelia-infected ticks. This strategy was employed as a mechanism to create antibodies against antigens presented by the natural route of tick transmission versus those presented by inoculation with cultured borreliae. One of the resultant antibodies reacted with a 17-kDa antigen from cultured B. burgdorferi, as seen by immunoblot analysis. This antibody was used to screen a B. burgdorferi genomic DNA lambda vector expression library, and an immunoreactive clone was isolated. DNA sequence analysis of this clone, containing a 2.7-kb insert, revealed several open reading frames. These open reading frames were found to be homologs of genes discovered as a multicopy gene family in the 297 strain of B. burgdorferi by Porcella et al. (S. F. Porcella, T. G. Popova, D. R. Akins, M. Li, J. D. Radolf, and M. V. Norgard, J. Bacteriol. 178:3293-3307, 1996). By selectively subcloning genes found in this insert into an Escherichia coli plasmid expression vector, the observation was made that the rev gene product was the protein reactive with the 17-kDa-specific monoclonal antibody. The rev gene product was found to be expressed in low-passage, but not in high-passage, B. burgdorferi B31. Correspondingly, the rev gene was not present in strain B31 genomic DNA from cultures that had been passaged >50 times. Serum samples from Lyme disease patients demonstrated an antibody response against the Rev protein. The generation of an anti-Rev response in Lyme disease patients, and in mice by tick bite inoculation, provides evidence that the Rev protein is expressed and immunogenic during the course of natural transmission and infection.

Amino Acid Sequence↗
PubMed2005

Synthetic salusins as cardiac depressors in rat.

Using bioinformatic analyses of full-length, enriched human cDNA libraries, we recently identified salusins, multifunctional related peptides ubiquitously expressed in major human tissues. Salusins cause transient and profound hypotension when injected intravenously to rats, the hypotensive effect of salusin-beta being especially striking. However, the mechanisms of this hypotensive action remain elusive. To determine whether salusins modulate cardiac function in rats, we studied serial changes of systemic hemodynamics and functions of isolated perfused working and nonworking hearts before and after salusin administration. Intravenous salusin-beta administration to intact anesthetized rats caused a temporary rapid, profound decrease in aortic blood flow concomitantly with hypotension and bradycardia without affecting systemic vascular resistance. Salusin-beta-induced hypotension and bradycardia were completely blocked by pretreatment with atropine, a muscarinic receptor antagonist, but not by propranolol. In isolated perfused working rat hearts, salusin-beta significantly decreased cardiac output, aortic flow, and stroke work. However, it did not affect coronary flow in isolated working and nonworking hearts. Our results indicate that salusins induce potent hypotension via negative inotropic and chronotropic actions. Salusin-beta promotes its actions by facilitating vagal outflows to the heart, whereas the negative inotropism of salusin-beta is also mediated via a direct myotropic effect.

Adenosine Triphosphatases↗
PubMed2002

Active heroin administration induces specific genomic responses in the nucleus accumbens shell.

Long-term drug-induced alterations in gene expression underlying neuroplasticity in the nucleus accumbens (NAc) may play a crucial role in relapse behavior in abstinent drug addicts. In this respect, stimulus-induced relapse behavior is considered as the retrieval of stored drug-related information. Because the NAc shell may determine the impact of external and internal stimuli on goal-directed behavior, we compared long-term gene expression in this brain region after active and passive administration of different drugs of abuse. We made use of a preselected set of transcripts that were down-regulated 3 wk after active i.v. heroin self-administration. We found that most of these transcripts were not down-regulated long after passive exposure to the opiate. Most of the active heroin administration-regulated transcripts were also down-regulated in the NAc shell following active cocaine administration (common denominators). As observed with passive administration of heroin, passive exposure to cocaine was found to be relatively ineffective in reducing the expression of these transcripts. This work reveals that active drug consumption during self-administration (instrumental learning) is a crucial psychological factor directing long-term genomic responses in the brain.

Animals↗
PubMed2001

Radiation-mediated control of drug delivery.

Clinical trials of radiotherapy to control drug delivery were initiated in 1999 at Vanderbilt University. The initial studies exploited the findings that platelets are activated in tumor blood vessels after high-dose irradiation as used in radiosurgery and high-dose-rate brachytherapy. Platelets labeled with 111In showed binding in tumor blood vessels. However, the platelet labeling process caused platelets to also accumulate in the spleen. That clinical trial was closed, and subsequent clinical trials targeted protein activation in irradiated tumor blood vessels. Preclinical studies showed that peptide libraries that bind within irradiated tumor blood vessels contained the peptide sequence Arg-Gln-Asp (RGD). RGD binds to integrin receptors (e.g., receptors for fibrinogen, fibronectin, and vitronectin). We found that the fibrinogen receptor (GPIIb/IIIa, alpha2bbeta3) is activated within irradiated tumor blood vessels. RGD peptidemimetics currently in clinical trials include GPIIb/IIIa antagonists and the platelet-imaging agent biapcitide. Biapcitide is an RGD mimetic that is labeled with 99Tc to allow gamma camera imaging of the biodistribution of the GPIIb/IIIa receptor in neoplasms of patients treated with radiosurgery. This study has shown that the schedule of administration of the RGD mimetic is crucial. The peptide mimetic must be administered immediately before irradiation, whereas the natural ligands to the receptor compete for biapcitide binding if biapcitide is administered after irradiation. The authors currently are conducting a dose deescalation study to determine the threshold dosage required for RGD mimetic binding to radiation activated receptor. Radiation-guided clinical trials have been initiated by use of high-dose-rate brachytherapy. In a separate trial, the pharmacokinetics of radiation-inducible gene therapy are being investigated. In this trial, the radiation-activated promoter Egr-1 regulates expression of the tumor necrosis factor alpha gene, which is administered by use of the attenuated adenovirus vector. The Ad.Egr-TNF (ADGV) gene is administered by intratumoral injection of vector followed by irradiation in patients with soft-tissue sarcomas. This review highlights recent findings in these phase I pharmacokinetic studies of radiation-controlled drug delivery systems.

Animals↗
PubMed2006

Aerosolized diuretics for preterm infants with (or developing) chronic lung disease.

BACKGROUND: Lung disease in preterm infants is often complicated with lung edema. OBJECTIVES: The aim of this review is to assess the risks and benefits of aerosolized diuretic administration in preterm infants with or developing chronic lung disease (CLD). Primary objectives are to assess effects on short term outcome (changes in need for oxygen or ventilatory support) and effects on long-term outcome. Secondary objectives are to assess changes in pulmonary mechanics and potential complications of therapy. SEARCH STRATEGY: We used the standard search method of the Cochrane Neonatal Review Group. We used the following keywords: { or } and , limited to and limited to or . We searched MEDLINE (1966 - 1998), EMBASE (1974 - 1998) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006). In addition, we hand searched several abstract books of national and international American and European Societies. The search of MEDLINE and of CENTRAL was last updated in March 2006. SELECTION CRITERIA: For the purpose of this analysis, we included trials in which preterm infants with or developing chronic lung disease and at least five days of age were all randomly allocated to receive an aerosolized loop diuretic. Eligible studies needed to assess at least one of the outcome variables defined a priori for this systematic review. Primary outcome variables included need for ventilator support, chronic lung disease, mortality and other important clinical outcomes. Secondary outcome variables included pulmonary mechanics and potential complications of therapy. DATA COLLECTION AND ANALYSIS: We used the standard method for the Cochrane Collaboration which is described in the Cochrane Collaboration Handbook. Two investigators extracted, assessed and coded separately all data for each study, using a form that was designed specifically for this review. Any disagreement was resolved by discussion. We combined parallel and cross-over trials and, whenever possible, transformed baseline and final outcome data measured on a continuous scale into change scores using Follmann's formula. MAIN RESULTS: We identified eight studies that met selection criteria. Most studies focused on pathophysiological parameters and did not assess effects on important clinical outcomes defined in this review or the potential complications of diuretic therapy. No study assessed the amount of diuretic effectively delivered to the patient. Furosemide was the only diuretic used in the eight studies included in this review. Among preterm infants < 3 weeks of age developing CLD, not enough information is available to assess the effect of aerosolized furosemide on outcome or lung function. Among infants > 3 weeks with CLD, a single aerosolized dose of 1 mg/kg of furosemide may transiently improve pulmonary mechanics. Not enough information is available to assess the effect of chronic administration of aerosolized furosemide on oxygenation and pulmonary mechanics. AUTHORS' CONCLUSIONS: In preterm infants > 3 weeks with CLD administration of a single dose of aerosolized furosemide improves pulmonary mechanics. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of aerosolized loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence.More double-blinded randomized trials are needed (1) to analyze factors likely to affect the response to aerosolized furosemide, e.g., washout period and delivery of furosemide to distal airways, and (2) to assess the effects of chronic administration of aerosolized furosemide on mortality, O2 dependency, ventilator dependency, length of hospital stay and long-term outcome.

Aerosols↗
PubMed2001

Techniques for preventing hypotension during spinal anaesthesia for caesarean section.

BACKGROUND: Maternal hypotension is the most frequent complication of a spinal anaesthetic for caesarean section with an incidence approaching 100%. Most workers define hypotension as a maternal systolic blood pressure below 70-80% of baseline recordings and/or an absolute value of < 90 -100mmHg. The frequent occurrence and rapid onset of hypotension during spinal anaesthesia has encouraged anaesthetists to try and prevent or minimise the associated maternal symptoms of nausea and vomiting during the establishment of the block. Untreated, severe hypotension can also pose serious risks to both mother (unconsciousness, pulmonary aspiration, apnoea or even cardiac arrest) and baby (impaired placental perfusion leading to hypoxia, fetal acidosis and neurological injury). A range of strategies is currently used to prevent or minimise hypotension but there is no established ideal technique. OBJECTIVES: To assess the relative efficacy and side effects of prophylactic interventions for hypotension following spinal anaesthesia for caesarean section. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group Trials Register, the Cochrane Controlled Trials Register, other databases and bibliographies of relevant papers are searched according to the strategy developed for the Pregnancy and Childbirth Group as a whole. Date of last search: May 2001. SELECTION CRITERIA: All published or unpublished randomised controlled trials that compare use of an intervention to prevent hypotension with placebo or alternative treatment in patients having spinal anaesthesia for caesarean section. DATA COLLECTION AND ANALYSIS: Trials identified from searching are assessed for inclusion by the same two reviewers independently. Studies are excluded from review for the following reasons: hypotension is not an outcome measure or clearly defined prior to administering a rescue treatment; randomisation is unsatisfactory; the spinal anaesthetic technique or dose of local anaesthetic is not controlled-for; and the intervention is implemented in response to a fall in blood pressure rather than for prevention. Statistical analyses use the Review Manager software for calculation of the treatment effect as represented by the relative risks and proportional and absolute risk reductions. MAIN RESULTS: Twenty trials meet the criteria for inclusion. Four of the twelve interventions reviewed are shown to reduce the incidence of hypotension under spinal anaesthesia for caesarean section: (1) crystalloid 20ml/kg vs control, Relative Risk (RR) 0.78 (95% confidence interval (CI) 0.6, 1.0); (2) pre-emptive colloid administration vs crystalloid, (RR) 0.54 (95% CI 0.37, 0.78); (3) ephedrine vs control, RR 0.70 (95% CI 0.57, 0.85); and (4) lower limb compression vs control, RR 0.75 (95% CI 0.59, 0.94). There are no significant differences in maternal or neonatal side effects in any of the comparisons studied. REVIEWER'S CONCLUSIONS: No studied intervention has been shown to eliminate the need to treat maternal hypotension during spinal anaesthesia for caesarean section. We are unable to draw any conclusions regarding adverse effects of the studied interventions, due to their probable low incidence and the small number of women studied. Further randomised controlled trials are recommended, in particular assessing a combination of the beneficial interventions, i.e. colloid or crystalloid preloading, parenteral ephedrine administration and leg compression with bandages, stockings or inflatable boots.

Anesthesia, Obstetrical↗
PubMed2001

Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush).

BACKGROUND: Anti-fungals are available for oral and intra-vaginal treatment of vulvovaginal candidiasis (thrush). OBJECTIVES: The primary objective of this review was to assess the relative effectiveness of oral versus intra-vaginal anti-fungals for the treatment of uncomplicated vulvovaginal candidiasis. The secondary objectives of the review were to assess the cost-effectiveness, safety and patient preference of oral versus intra-vaginal anti-fungals. SEARCH STRATEGY: The following sources were searched: The Cochrane Library (Issue 4, 1999), MEDLINE (January 1985 to May 2000), EMBASE (January 1980 to January 2000) and the Cochrane Collaboration Sexually Transmitted Disease Group Specialised Register of Controlled Trials. The reference lists of retrieved articles were reviewed manually. The manufacturers of anti-fungals available in the UK were contacted. SELECTION CRITERIA: ~Bullet~Randomised controlled trials published in any language. ~Bullet~Trials had to compare at least one oral anti-fungal with one intra-vaginal anti-fungal. ~Bullet~Women (aged 16 years or over) with uncomplicated vulvovaginal candidiasis. ~Bullet~The diagnosis of vulvovaginal candidiasis to be made mycologically (i.e. a positive culture and / or microscopy for yeast). ~Bullet~Trials were excluded if they solely involved subjects who were HIV positive, immunocompromised, pregnant, breastfeeding or diabetic. ~Bullet~The primary outcome measure was clinical cure. DATA COLLECTION AND ANALYSIS: Duplicate scrutiny was performed of the titles and abstracts of the electronic search results. Full article formats of all selected abstracts were retrieved and independently assessed by two reviewers. Independent duplicate abstraction was performed by four reviewers. Disagreements regarding trial inclusion or data abstraction were resolved by discussion between the reviewers. Odds ratios were pooled using the random effects model. Chi-squared tests with a p-value of less than 0.1 indicated heterogeneity in the results. MAIN RESULTS: Seventeen trials are included in the review, reporting 19 oral versus intra-vaginal anti-fungal comparisons. No statistically significant differences were shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short term (OR 1.00 (95% CI, 0.72 to 1.40)) and long term (OR 1.03 (95% CI, 0.72 to 1.49)) follow-up. No statistically significant differences for mycological cure were observed between oral and intra-vaginal treatment at short term (OR 1.20(95% CI, 0.87 to 1.65)) or long term follow-up (OR 1.30 (95% CI, 0.99 to 1.71)). Two trials each reported one withdrawal from treatment due to an adverse reaction. Treatment preference data were poorly reported. REVIEWER'S CONCLUSIONS: No differences exist in terms of the relative effectiveness (measured as clinical and mycological cure) of anti-fungals administered by the oral and intra-vaginal routes for the treatment of uncomplicated vaginal candidiasis. No definitive conclusion can be made regarding the relative safety of oral and intra-vaginal anti-fungals for uncomplicated vaginal candidiasis. The oral route of administration is the preferred route for anti-fungals for the treatment of vulvovaginal candidiasis. The decision to prescribe or recommend the purchase of an anti-fungal for oral or intra-vaginal administration should take into consideration: safety, cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications: if women are purchasing their own treatment, they should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of oral anti-fungal administration is worth the gain in convenience, if this is the patient's preference.

Administration, Intravaginal↗
PubMed1996

Mitochondrial involvement in schizophrenia and other functional psychoses.

Gene expression has been studied in post-mortem frontal cortex samples from patients who had suffered from schizophrenia and depressive illness. mRNA was extracted and characterised by translation and separation of the products by 2D gel electrophoresis. Post-mortem artefacts and the agonal experience did not affect the size distribution or amount of specific translation products. Four expression products were specifically reduced in samples from schizophrenics compared with normals. The expression of six products was altered in affective disorder, one in common with schizophrenia, two the same as in schizophrenia but increased. cDNA libraries were produced from the mRNA samples and 5 clones present at abnormal levels in schizophrenia identified by differential screening, isolated and sequenced. All the sequences encode mitochondrial transcripts; four encode mitochondrial rRNA and one the amino acid sequence of cytochrome oxidase sub-unit II. Increased cytochrome oxidase transcripts were found in a further set of mRNA extracts from schizophrenic patients including two who had not received neuroleptic medication. The effects of neuroleptic administration as exemplified by alpha-flupenthixol compared with the ineffective beta-flupenthixol were studied in experimental animals. It was found that 13 out of 28 clones whose levels were altered were mitochondrial in origin including rRNA, COX I & II and the NADH-Q reductase. Those encoding respiratory enzymes were at abnormally low levels as a result of alpha-flupenthixol administration. Measurements of the enzymic activity of cytochrome c oxidase in post-mortem frontal cortex of schizophrenics did not indicate any differences in overall activity but there was a decreased sensitivity to azide that was abolished by neuroleptics. Studies on NADH-cytochrome c reductase showed that schizophrenics whether medicated or not had a reduced rotenone sensitive activity that was compensated for by increased rotenone insensitive activity. We conclude that changes in mitochondrial gene expression are involved in schizophrenia and probably other functional psychoses.

Adult↗
PubMed2003

Identification of a synovial fibroblast-specific protein transduction domain for delivery of apoptotic agents to hyperplastic synovium.

Synovial hyperplasia, resulting in erosion of cartilage and bone, represents one of the major pathologies associated with rheumatoid arthritis. To develop an approach for efficient delivery of proteins or agents to synovium to induce targeted apoptosis of hyperplastic synovial tissue, we have screened an M13 peptide phage display library for synovial-specific transduction peptides. We identified a novel synovial-targeted transduction peptide, HAP-1, which is able to facilitate specific internalization of protein complexes into human and rabbit synovial cells in culture and rabbit synovial lining in vivo. HAP-1 and a non-tissue-specific cationic protein transduction domain, PTD-5, were fused to an antimicrobial peptide, (KLAK)(2), to generate two proapoptotic peptides termed DP2 and DP1, respectively. Administration of these peptides was able to induce apoptosis of rabbit and human synovial cells in culture, with DP2 inducing synovial cell-specific apoptosis. Intra-articular injection of DP1 and DP2 into arthritic rabbit joints with synovial hyperplasia induced extensive apoptosis of the hyperplastic synovium, while reducing the leukocytic infiltration and synovitis. These results suggest that proapoptotic peptides and, in particular, DP2 can be clinically useful for treatment of synovial hyperplasia, as well as inflammation. Moreover, the results demonstrate the feasibility of identifying tissue-specific transduction peptides capable of mediating efficient transduction in vivo.

Amino Acid Sequence↗
PubMed2003

Oxidative stress and aging--the use of superoxide dismutase/catalase mimetics to extend lifespan.

To date, more than 40 genes have been identified in the nematode Caenorhabditis elegans, which, when mutated, lead to an increase in lifespan. Of those tested, all confer an increased resistance to oxidative stress. In addition, the lifespan of C. elegans can also be extended by the administration of synthetic superoxide dismutase/catalase mimetics. These compounds also appear to confer resistance to oxidative damage, since they protect against paraquat treatment. The protective effects of these compounds are apparent with treatment during either development or adulthood. These findings have demonstrated that pharmacological intervention in the aging process is possible and that these compounds can provide important information about the underlying mechanisms. To date, such interventions have targeted known processes rather than screening compound libraries because of the limitations of assessing lifespan in nematodes. However, we have recently developed a microplate-based assay that allows for a rapid and objective score of nematode survival at rates many times higher than previously possible. This system now provides the opportunity to perform high-throughput screens for compounds that affect nematode survival in the face of acute oxidative stress and will facilitate the identification of novel drugs that extend nematode lifespan.

Aging↗
PubMed1994

Institutional constraints to building social science capability in public health research: a case study from Indonesia.

The promotion of social sciences capabilities in public health research in universities frequently encounters unexpected barriers. This paper argues that, in Indonesia, historic factors and institutional structures of public health research have created constraints to success in public health research and international technical assistance. Donors are often frustrated by apparent inconsistencies between agreed intentions and the subsequent behaviour of recipient colleagues, thus resulting in poor relations and failure of collaborative links. For social sciences to be integrated into public health research, assistance is needed in graduate education, library development, computerisation, and research methodology. Contributions in these areas may be ineffectual if they are not preceded or accompanied by efforts by recipients to reform or circumvent existing institutional weaknesses. Some important barriers to the development of research capabilities in Indonesia are beyond the control of individual faculties of public health, or even universities, and are affected by regulations and budgeting procedures of the National Department of Education and Culture, or the civil service administration. There are, however, changes that can be made at faculty or university level to encourage a more productive 'research culture' and promote linkages between the social and health sciences.

Humans↗
PubMed2005

Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist.

The aim of the present study was to identify specific alpha(v)beta3/alpha(v)beta5 integrin antagonists active on tumor-induced angiogenesis. To this purpose, in vitro integrin-binding assays were used to screen a library of conformationally constrained bicyclic lactam Arg-Gly-Asp-containing pseudopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta3 and alpha(v)beta5 integrins with negligible interacting with alpha5beta1 integrin. In all the assays, ST1646 was equipotent to or more potent than the well-characterized integrin antagonists c(RGDfV) and cyclo(Arg-Gly-Asp-d-Phe-[NMe]Val) (EMD121974). In the chorioallantoic membrane assay, topical administration of ST1646 was able to prevent the angiogenic responses elicited by recombinant fibroblast growth factor-2 or vascular endothelial growth factor. In addition, systemic administration of ST1646 in mice exerted a significant antiangiogenic activity on neovascularization triggered by mammary carcinoma MDA-MB435 cells implanted s.c. in a dorsal air sac via a (Millipore Filter Corporation, Bedford, MA) chamber. Moreover, ST1646 delivery via an osmotic pump inhibited the growth and vascularization of tumor xenografts originating from the injection of alpha(v)beta3/alpha(v)beta5-expressing human ovarian carcinoma cells in nude mice. In agreement with the biochemical and pharmacologic studies, Monte Carlo/Stochastic Dynamics simulation showed that the bicyclic scaffold in ST1646 forced the compound to assume a preferred conformation superimposable to the X-ray conformation of alpha(v)beta3-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-alpha(v)beta3 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta3 integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta3/alpha(v)beta5 integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.

Animals↗