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Biomedical subjects

R Gilbert

Publications and source records attributed to R Gilbert.

At least 19 recordsLinked to original sources
PubMed2006

Symptomatic toxoplasma infection due to congenital and postnatally acquired infection.

AIMS: To determine the incidence and severity of symptomatic toxoplasma infection presenting during childhood due to congenital or postnatally acquired infection. METHODS: Between 2002 and 2004, newly diagnosed children (<16 years) with signs or symptoms of congenital or ocular toxoplasmosis were reported by clinicians to the British Paediatric and Ophthalmic Surveillance Units or by toxoplasma referral laboratories. Confirmed cases were estimated to have a greater than 50% probability of congenital and/or ocular toxoplasmosis, based on clinical and serological findings. RESULTS: Thirty eight children had confirmed toxoplasma infection. Twenty two (58%) were classified with congenital infection (cumulative incidence for England and Wales 1.62[corrected]/100,000 live births; 95% CI 0.85[corrected] to 2.83[corrected]), of whom 2 (9%) were stillborn, 7 (32%) live births had intracranial abnormalities and/or developmental delay (5 of whom had retinochoroiditis), and 10 (45%) had retinochoroiditis with no other abnormalities reported. A further 16 (42%) children were classified as infected after birth; all had retinochoroiditis. CONCLUSIONS: The low burden of symptomatic congenital toxoplasmosis combined with the lack of evidence of an effective treatment support current policy not to offer prenatal or neonatal screening for toxoplasma infection. Primary prevention strategies need to address acquisition of infection in childhood which accounts for half the ocular disease due to toxoplasma infection in children in the UK and Ireland.

Abortion, Spontaneous↗
PubMed2006

Importance of renin in blood pressure regulation and therapeutic potential of renin inhibition.

Despite improvements in its detection and treatment, hypertension remains a significant public health problem worldwide. In recent years, many international hypertension societies and organisations have set increasingly rigorous blood pressure (BP) targets, with the aim of reducing cardiovascular complications, and this has in turn necessitated the use of more antihypertensive medications to reach these targets in individual patients. There is therefore an ongoing need to develop antihypertensive drugs with new mechanisms of action. Renin inhibitors represent a novel class of compounds which offer considerable promise as BP-lowering agents. Here, we review the rationale for renin inhibition as a therapeutic target and examine the preclinical and clinical evidence for the antihypertensive effectiveness of the renin inhibitors.

Antihypertensive Agents↗
PubMed2005

Association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth.

OBJECTIVE: To determine the association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth. DESIGN: Multicentre prospective cohort study. SETTING: Ten European centres offering prenatal screening for toxoplasmosis. POPULATION: Deliveries after 23 weeks of gestation in 386 women with singleton pregnancies who seroconverted to toxoplasma infection before 20 weeks of gestation. Deliveries after 36 weeks in 234 women who seroconverted at 20 weeks or later, and tested positive before 37 weeks. METHODS: Comparison of infected and uninfected births, adjusted for parity and country of birth. MAIN OUTCOME MEASURES: Differences in gestational age at birth, birthweight and birthweight centile. RESULTS: Infected babies were born or delivered earlier than uninfected babies: the mean difference for seroconverters before 20 weeks was -5.4 days (95% CI: -1.4, -9.4), and at 20 weeks or more, -2.6 days (95% CI: -0.5, -4.7). Congenital infection was associated with an increased risk of preterm delivery when seroconversion occurred before 20 weeks (OR 4.71; 95% CI: 2.03, 10.9). No significant differences were detected for birthweight or birthweight centile. CONCLUSION: Babies with congenital toxoplasmosis were born earlier than uninfected babies but the mechanism leading to shorter length of gestation is unknown. Congenital infection could precipitate early delivery or prompt caesarean section or induction of delivery. We found no evidence for a significant association between congenital toxoplasmosis and reduced birthweight or small for gestational age birth.

Abortion, Induced↗
PubMed2005

The prevention of neonatal group B streptococcal disease: a report by a working group of the Medical Screening Society.

Streptococcus agalactiae, or Lancefield group B streptococcus (GBS), is the most frequent cause of serious bacterial sepsis, including neonatal meningitis, in UK neonates. Early-onset neonatal GBS infection, but not late-onset, can be prevented by screening to identify high-risk pregnancies and administering penicillin during delivery. A vaccine has been developed as an alternative means of prevention but it is awaiting a randomized trial before being available for general use. In this review we examine the published literature to assess the morbidity and mortality attributable to neonatal GBS infection, quantify the screening performance of the two alternative modes of screening (microbiological and risk factor based), review the evidence on the efficacy of the vaccine, and estimate the numbers of deaths and cases of serious disability that each strategy in turn might prevent in the UK, in order to assess the most effective means of prevention for the UK.

Antibiotic Prophylaxis↗
PubMed2003

Effect of timing and type of treatment on the risk of mother to child transmission of Toxoplasma gondii.

OBJECTIVE: To determine the effects on mother to child transmission of the timing and type of prenatal treatment, taking into account gestational age at maternal seroconversion. DESIGN: Prospective cohort study. SETTING: European centres offering prenatal screening for toxoplasmosis. POPULATION: Children born to a cohort of pregnant women with toxoplasma infection. METHODS: We determined the effects on mother to child transmission of the interval between seroconversion and start of treatment (treatment delay), and the type of treatment, taking into account gestational age at maternal seroconversion. MAIN OUTCOME MEASURE: Congenital infection status confirmed by toxoplasma IgG results at one year postnatal age. RESULTS: Of 1208 women analysed, 72% were first prescribed spiramycin, 19% pyrimethamine-sulphonamide and 9% (mostly infected during the last trimester) were untreated. The odds ratios for mother to child transmission for all women treated after a delay of four to seven weeks was 0.77 (95% CI 0.34-1.69), and after eight weeks or more was 1.33 (0.56-2.89) compared with less than four weeks. The odds ratio per week of treatment delay was 1.01 (0.93-1.08). There was no evidence that transmission risk differed in women first treated with pyrimethamine-sulphonamide versus spiramycin: odds ratio 1.10 (0.63-1.91) or in untreated versus treated women: odds ratio 0.57 (0.27-1.17). CONCLUSION: We were unable to demonstrate a beneficial effect of the timing or type of prenatal treatment on the risk of mother to child transmission but we could not exclude a clinically important effect. Randomised controlled trials are required to determine the effect of prenatal treatment on mother to child transmission.

Adult↗
PubMed2003

Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer.

Utrophin is highly homologous and structurally similar to dystrophin, and in gene delivery experiments in mdx mice was able to functionally replace dystrophin. We performed mini-utrophin gene transfer in Golden Retriever dogs with canine muscular dystrophy (CXMD). Unlike the mouse model, the clinicopathological phenotype of CXMD is similar to that of Duchenne muscular dystrophy (DMD). We injected an adenoviral vector expressing a synthetic utrophin into tibialis anterior muscles of newborn dogs affected with CXMD and examined transgene expression by RNA and protein analysis at 10, 30 and 60 days postinjection in cyclosporin-treated and -untreated animals. Immunosuppression by cyclosporin was required to mitigate the immune response to viral and transgene antigens. RT-PCR analysis showed the presence of the exogenous transcript in the muscle of cyclosporin-treated and -untreated animals. The transgenic utrophin was efficiently expressed at the extrajunctional membrane in immunosuppressed dogs and this expression was stable for at least 60 days. We found reduced fibrosis and increased expression of dystrophin-associated proteins (DAPs) in association with muscle areas expressing the utrophin minigene, indicating that mini-utrophin can functionally compensate for lack of dystrophin in injected muscles. For this reason, utrophin transfer to dystrophin-deficient muscle appears as a promising therapeutic approach to DMD.

Adenoviridae↗
PubMed2001

Dystrophin expression in muscle following gene transfer with a fully deleted ("gutted") adenovirus is markedly improved by trans-acting adenoviral gene products.

Helper-dependent adenoviruses (HDAd) are Ad vectors lacking all or most viral genes. They hold great promise for gene therapy of diseases such as Duchenne muscular dystrophy (DMD), because they are less immunogenic than E1/E3-deleted Ad (first-generation Ad or FGAd) and can carry the full-length (Fl) dystrophin (dys) cDNA (12 kb). We have compared the transgene expression of a HDAd (HDAdCMVDysFl) and a FGAd (FGAdCMV-dys) in cell culture (HeLa, C2C12 myotubes) and in the muscle of mdx mice (the mouse model for DMD). Both vectors encoded dystrophin regulated by the same cytomegalovirus (CMV) promoter. We demonstrate that the amount of dystrophin expressed was significantly higher after gene transfer with FGAdCMV-dys compared to HDAdCMVDysFl both in vitro and in vivo. However, gene transfer with HDAdCMVDysFl in the presence of a FGAd resulted in a significant increase of dystrophin expression indicating that gene products synthesized by the FGAd increase, in trans, the amount of dystrophin produced. This enhancement occurred in cell culture and after gene transfer in the muscle of mdx mice and dystrophic golden retriever (GRMD) dogs, another animal model for DMD. The E4 region of Ad is required for the enhancement, because no increase of dystrophin expression from HDAdCMVDysFl was observed in the presence of an E1/E4-deleted Ad in vitro and in vivo. The characterization of these enhancing gene products followed by their inclusion into an HDAd may be required to produce sufficient dystrophin to mitigate the pathology of DMD by HDAd-mediated gene transfer.

Adenoviridae↗
PubMed2001

Simultaneous determination of dissolved gases and moisture in mineral insulating oils by static headspace gas chromatography with helium photoionization pulsed discharge detection.

This paper presents the development of a static headspace capillary gas chromatographic method (HS-GC) for simultaneously determining dissolved gases (H2, O2, N2, CO, CO2, CH4, C2H6, C2H4, C2H2, C3H8) and moisture from a unique 15-mL mineral oil sample. A headspace sampler device is used to equilibrate the sample species in a two-phase system under controlled temperature and agitation conditions. A portion of the equilibrated species is then automatically split-injected into two chromatographic channels mounted on the same GC for their separation. The hydrocarbons and the lighter gases are separated on the first channel by a GS-Q column coupled with a MolSieve 5-A column via a bypass valve, while the moisture is separated on the second channel using a Stabilwax column. The analytes are detected by using two universal pulsed-discharge helium ionization detectors (PDHID). The performance of the method was established using equilibrated vials containing known amounts of gas mixture, water, and blank oil. The signal is linear over the concentration ranges normally found for samples collected from open-breathing power transformers. Determination sensitivity varies with the nature of the species considered with values as high as 21 500 A x 10(-9) s (microg/ g)(-1) for H2O, 46-216 A x 10(-9) s (microL/L)(-1) for the hydrocarbons and carbon oxides, and as low as 8-21 A x 10(-9) s (microL/L)(-1) for the O2 and N2 permanent gases. The detection limit of the method is between 0.08 and 6 microL/L for the dissolved gases, except for O2, N2, and CO2, where higher values are observed due to air intrusion during sampler operations, and 0.1 microg/g for the dissolved water. Ten consecutive measurements in the low and high levels of the calibration curves have shown a precision better than 12% and 6%, respectively, in all cases. A comparison study between the HS-GC method and the ASTM standard procedures on 31 field samples showed a very good agreement of the results. The advantages of configuring the arrangement with two PDHID over the conventional flame ionization and thermal conductivity detectors were clearly demonstrated.

Journal Article↗
PubMed2001

Bias assessment of current technologies used for the determination of low levels of moisture in mineral oil samples.

The problem in the current debate on the accuracy of Karl Fischer (KF) titrations lies in the fact that coulometry is being compared to volumetry on mineral oil samples for which the true moisture content is unknown. To clarify this point, dehydrated oil samples equilibrated under known temperature and relative humidity conditions and equilibrated oil samples containing known amounts of added moisture were used to assess the accuracy of the determinations. In addition, the measurements were extended to other techniques given that it is unlikely that they would be affected by the same phenomenon causing the KF systematic errors. The samples sent to different laboratories were analyzed by headspace/capillary gas chromatography, gas-phase H2 sensor, oil-phase or gas-phase RH sensors, KF coulometric titration with direct or indirect injection, and KF volumetric titration using a standard or NIST modified procedure. The laboratory comparison showed that with the exception of 4 techniques out of 10 that were tested, the measurements gave results in the expected concentration range. Considering the exceptions, two techniques based on volumetric titration yielded results tainted with an important positive bias for both sample types. This bias, tentatively associated with the high iodine end point concentration used by these systems, was estimated at approximately 22 ppm under the conditions applied by NIST. On the other hand, the two RH sensors showed a marked tendency to underestimate the value of the samples containing high moisture content. In this case, a loss of analyte through wall adsorption during the time required to achieve steady-state conditions in the measuring chamber seems to be at the origin of the negative biases.

Journal Article↗
PubMed2001

Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia.

BACKGROUND: Iron deficiency and iron deficiency anaemia (IDA) are common in young children. It has been suggested that the lack of iron may have important effects on children's psychomotor development and cognitive function. OBJECTIVES: To determine the effects of iron therapy on psychomotor development and cognitive function in iron deficient children less than 3 years of age. SEARCH STRATEGY: The following databases were searched: COCHRANE LIBRARY (2000 ISSUE 4) MEDLINE (1966-August 2000) EMBASE (1980-August 2000) Latin American Database (LILACS) PsycLIT Journal articles (1974-August 2000) PsycLIT Chapters and Books (1987-August 2000) The references of identified trials and of important review articles were scrutinised. Citation searches on trials from the primary search were performed within the Science Citation Index. Key authors were contacted. SELECTION CRITERIA: Studies were included if children less than 3 years of age with evidence of iron deficiency anaemia were randomly allocated to iron or iron and vitamin C versus a placebo or vitamin C alone and assessment of developmental status or cognitive function was carried out using standardised tests by observers blind to treatment allocation. DATA COLLECTION AND ANALYSIS: Abstracts and titles of studies identified on searches of electronic databases were read to determine whether they might meet the inclusion criteria. Full copies of those possibly meeting these criteria from electronic or other searches were assessed by two independent reviewers. Differences of opinion about suitability for inclusion were resolved by discussion. Data were analysed separately depending on whether participants had iron assessments were performed within one month of beginning iron therapy or later. MAIN RESULTS: Five trials, including 180 children with IDA, examined the effects of iron therapy on measures of psychomotor development between 5 and 11 days of commencement of therapy. Data from four trials could be pooled. The pooled difference in pre to post treatment change in Bayley Scale PDI between iron treated and placebo groups was -3.2 (95%CI -7.24, 0.85) and in Bayley Scale MDI, 0.55 (95% CI -2.84, 1.75). Two studies, including 160 randomised children with IDA, examined the effects of iron therapy on measures of psychomotor development more than 30 days after commencement of therapy. Aukett et al reported the mean number of skills gained after two months of iron therapy, using the Denver test. The intervention group gained 0.8 (95% CI -0.18, 1.78) more skills on average than the control group. Idjrandinata et al reported that the difference in pre to post treatment change in Bayley Scale PDI between iron treated and placebo groups after 4 months was 18.40 (95%CI 10.16, 26.64) and in Bayley Scale MDI, 18.80 (95% CI 10.19, 27.41). REVIEWER'S CONCLUSIONS: There is no convincing evidence that iron treatment of young children with IDA has an effect on psychomotor development discernable within 5-11 days. The effect of longer term treatment remains unclear but the data would be compatible with clinically significant benefit. There is urgent need for further randomised controlled trials with long term follow up.

Anemia, Iron-Deficiency↗
PubMed2001

Inhibition of leukotriene function can modulate particulate-induced changes in bone cell differentiation and activity.

Aseptic loosening remains the major problem facing arthroplasty longevity with particulates from component materials touted as the cause of periprosthetic osteolysis. Proposed mechanisms in aseptic bone loss include: increased resorption, increased differentiation of osteoclasts (and/or macrophages locally), and decreased osteoblastic bone formation. Leukotrienes participate in osteoclastic bone resorption. We investigated inhibiting leukotrienes synthesis, using ICI 230487, to ameliorate the effects of particulates on osteoclast pit formation and also assessed the effects of alendronate, a bisphosphonate, on pit formation. Three particulates were used: ultra high molecular weight polyethylene (UHMWPE), polymethylmethacrylate (PMMA) and hydroxyapatite (HA). Osteoclast resorption was increased with UHMWPE, PMMA, and HA particles. Interventions with alendronate and ICI 230487 reduced particulate-induced osteoclast resorption. Both ICI 230487 and alendronate reduced osteoclast numbers at higher doses. To assess the effect of particulates on osteoclast and macrophage differentiation, mouse bone marrow was cultured and stained for tartrate resistant acid phosphatase colonies (TRAP+, osteoclasts) and nonspecific esterase positive colonies (NSE+, macrophage precursors). Particulates increased both TRAP+ and NSE+ colony formation. These increases were inhibited by ICI 230487. Particulates also inhibited osteoblast function assessed by the development of mineralized nodules and alkaline phosphatase positive (AP+) colony area. ICI 230487 partly protected osteoblast function from this particulate effect. Blockade of leukotriene production may prove a useful therapeutic intervention for particulate-induced aseptic loosening by inhibiting resorptive activity, reducing the pro-inflammatory cell populations induced and recruited by these particulates, as well as ameliorating the negative effects of inflammatory mediators on osteoblast function.

Animals↗
PubMed2001

Effects of electrochemotherapy with bleomycin on normal liver tissue in a rat model.

Preliminary studies that used electric pulses in vivo to facilitate entry of chemotherapeutic agents into tumour cells resulted in a 69% complete response rate for hepatocellular carcinoma in rats. This success motivated a focused investigation to define the adverse effects of this treatment on normal liver tissue. Bleomycin doses ranging from 0.5 to 2.5 U and electric fields from 500 to 2250 V/cm were investigated. Electrical treatment was administered using an array of six needles arranged in a circular pattern. Necrosis and four other histological parameters were examined 14 and 56 days after treatment. Results indicated that treatment effects were localised to the volume of treated tissue. These parameters, at both time points, were not significantly altered for liver tissue that was treated with all drug doses and electric fields of 1250 V/cm and below. Only the combination of more intense electric pulses with bleomycin produced adverse histological events in the form of localised liver necrosis at day 14. These effects were not visible at day 56. Liver function was normal through all of the treatment except for an elevation of several enzymes 1 day post-treatment.

Animals↗
PubMed2001

Ecological comparison of the risks of mother-to-child transmission and clinical manifestations of congenital toxoplasmosis according to prenatal treatment protocol.

We compared the relative risks of mother-to-child transmission of Toxoplasma gondii and clinical manifestations due to congenital toxoplasmosis associated with intensive prenatal treatment in Lyon and Austria, short term treatment in 51% of Dutch women, and no treatment in Danish women. For each cohort, relative risks were standardized for gestation at seroconversion. In total, 856 mother-child pairs were studied: 549 in Lyon, 133 in Austria, 123 in Denmark and 51 in The Netherlands. The relative risk for mother-to-child transmission compared to Lyon was 1.24 (95% CI: 0.88, 1.59) in Austria; 0.59 (0.41, 0.81) in Denmark; and 0.65 (0.37, 1.01) in The Netherlands. Relative risks for clinical manifestations compared with Lyon (adjusted for follow-up to age 3 years) were: Austria 0.19 (0.04, 0.51); Denmark 0.60 (0.13, 1.08); and The Netherlands 1.46 (0.51, 2.72). There was no clear evidence that the risk of transmission or of clinical manifestations was lowest in centres with the most intensive prenatal treatment.

Anti-Bacterial Agents↗
PubMed2001

Low incidence of toxoplasma infection during pregnancy and in newborns in Sweden.

To estimate the burden of disease due to congenital toxoplasmosis in Sweden the incidence of primary infections during pregnancy and birth prevalence of congenital toxoplasmosis in 40,978 children born in two regions in Sweden was determined. Women possibly infected during pregnancy were identified based on: 1, detection of specific IgG based on neonatal screening of the phenylketonuria (PKU) card blood spot followed by retrospective testing of stored prenatal samples to detect women who acquired infection during pregnancy and follow up of their children to 12 months: 2, detection of specific IgM on the PKU blood spot. The birth prevalence of congenital toxoplasmosis was 0.73/10,000 (95 % CI 0.15-2.14) (3/40,978). The incidence of primary infection during pregnancy was 5.1/10,000 (95% CI 2.6-8.9) susceptible pregnant women. The seroprevalence in the southern part was 25.7% and in the Stockholm area 14.0%. The incidence of infection during pregnancy was low, as the birth prevalence of congenital toxoplasmosis. Neonatal screening warrants consideration in view of the low cost and feasibility.

Algorithms↗
PubMed2001

In vivo electroporation using an exponentially enhanced pulse: a new waveform.

In vivo electroporation is currently accomplished by one of two types of common waveforms: exponential decay or square-wave pulses. The purpose of this report is to present a new electroporation waveform, the exponentially enhanced pulse (EEP). Pulsing protocols including the EEP resulted in high levels of luciferase expression in muscle and skin, equal to or greater than expression resulting from low-voltage, millisecond square-wave pulses. This high level of expression requires fewer pulses when using an EEP protocol. Therefore, similar or greater plasmid DNA expression levels are obtained using fewer pulses with the EEP protocol than with current protocols. This is the first report of this new waveform and shows the success of using protocols employing the EEP to deliver plasmid DNA to various tissue types.

Animals↗