Ambivalence, sexual pleasure and the acceptability of microbicidal products in south-west Uganda.
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Condoms↗
Biomedical subjects
J Wilkinson
Publications and source records attributed to J Wilkinson.
Identification of a novel mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency.
A novel mutation was identified in two unrelated patients with medium-chain acyl-CoA dehydrogenase deficiency. First, a 19-year-old Caucasian female presented with a devastating illness, resulting in sudden death in adulthood which is unusual. The second patient, now a 3.5-year-old male, presented at 17 months of age with a hypoglycemic seizure and dehydration. Sequence analysis revealed a novel mutation G617T in exon 8 resulting in an arginine to leucine substitution at codon 206 (R206L). Both patients were compound heterozygous for this G617T and the common mutation A985G.
Acyl-CoA Dehydrogenase↗
Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.
We describe here eleven different mutations in SPINK5, encoding the serine protease inhibitor LEKTI, in 13 families with Netherton syndrome (NS, MIM256500). Most of these mutations predict premature termination codons. These results disclose a critical role of SPINK5 in epidermal barrier function and immunity, and suggest a new pathway for high serum IgE levels and atopic manifestations.
Abnormalities, Multiple↗
Phenothiazine, butyrophenone, and other psychotropic medication poisonings in children and adolescents.
OBJECTIVE: To describe the presentation, epidemiology, management, and outcome of phenothiazine and butyrophenone ingestions in children requiring hospitalization. METHOD: Retrospective case series in two pediatric hospitals. RESULTS: Eighty-six cases were identified among 83 patients. The majority (69.7%) of ingestions occurred in children <6 years of age and there was no gender predominance. These ingestions were more common in African Americans (65.1%). They occurred more commonly in the patient's (64.0%) or a relative's (22.1%) home and haloperidol and thioridazine accounted for 58.1% of exposures. Depressed levels of consciousness and dystonia were the most common presenting signs, present in 90.7% and 51.2% of patients, respectively. Miosis occurred in only 13.9% of the patients. Fluid boluses were administered to 28.7% of the patients but about a quarter of these had coingested potentially cardiotoxic drugs. In addition, 2 of the 12 (13.9%) patients with abnormal electrocardiograms had also ingested potentially cardiotoxic drugs. Numerous diagnostic tests were performed in these patients including electrolyte panels (80.2%), complete blood counts (69.8%), liver function tests (31.4%), serum osmolality (20.9%), blood cultures (10.5%), lumbar punctures (17.4%), head computed tomographies (15.1%), and electroencephalograms (3.5%). The median length of hospitalization was 1.78 (range 1-9) days and there were no deaths. Patients presenting with dystonias were more likely to have extensive diagnostic testing for neurologic disease than those presenting without dystonias. CONCLUSION: The presentation of phenothiazine and butyrophenone ingestions in children and adolescents may be nonspecific and confounded by coingestants. Patients with dystonias had more extensive neurologic testing than patients without dystonias, suggesting that physicians may not recognize dystonias as a clinical finding characteristic of phenothiazine or butyrophenone exposure.
Accidents, Home↗
Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping.
Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.
Adolescent↗
Pasteurella multocida meningitis in an adult: case report.
Pasteurella multocida is known to form part of the normal flora in the nasopharynx or gastrointestinal tract in many domestic and wild animals. Most human P multocida infections are soft tissue infections caused by dog or cat bites. Less commonly this bacterium is associated with infections affecting other organ systems of man. A case of fatal P multocida meningitis discovered at the necropsy of a 52 year old man is described. P multocida is an unusual causative agent of meningitis which tends to affect those at the extremes of age.
Fatal Outcome↗
Linkage analysis of markers on chromosome 11q13 with asthma and atopy in a United Kingdom population.
Previous studies have suggested that atopy is linked to the beta chain of the high affinity IgE receptor (Fcepsilon R1-beta) on chromosome 11q13. Fcepsilon R1-beta polymorphisms, I181L, V183L, and E237G, are reported to be associated with asthma and atopy. The aim of this study was to investigate linkage to Fcepsilon R1-beta in a UK population and to assess the frequency of the polymorphisms and their association with asthma and atopy. A sample of 131 families was recruited at random with a sample of 109 families ascertained via an asthmatic proband. Each subject completed a written and video-assisted questionnaire and underwent bronchial challenge and skin prick testing. Serum total and specific IgE levels were measured. Quantitative scores were derived for asthma and atopy using principal component analysis. Four microsatellite markers were genotyped, including Fcepsilon R1-beta. The frequency of the I181L and V183L polymorphisms were determined by sequencing, and the E237G polymorphism was determined using the amplification refractory mutation system. We found no evidence for linkage to Fcepsilon R1-beta and only weak evidence for linkage to the less informative marker E237G. We found no examples of the I181L/V183L polymorphism in our population sample. Our study has failed to strengthen the evidence for a candidate gene on chromosome 11q13.
Adult↗
An acceptability study of female-controlled methods of protection against HIV and STDs in south-western Uganda.
We aimed to assess the acceptability of a variety of formulations of female-controlled methods of protection against HIV and STDs among men and women in south-western Uganda. Pilot interviews were carried out with 50 men and 55 women and 25 focus group discussions (FGDs) were held with 138 women and 42 men. The female condom, foaming tablets, sponge, foam, gel and film were demonstrated to 146 women and 35 of their male partners, who then tried out 2 of the products. They were interviewed 7 times during the course of 5 months. At the end experiences were evaluated during a second series of FGDs. Sixty-five (45%) women completed the trial. The main reasons for non-completion were related to geographical mobility. Product preference after the initial demonstration was similar to that at the end of the trial. The most popular formulations were the sponge (25% of the women), foaming tablets (23%), and the female condom (19%). The foam was of medium popularity (16%). The gel (9%) and film (7%) were least popular. Ten per cent of the women and 14% of the men reported products interfering with sexual enjoyment; 24% of the women and 67% of the men said products increased enjoyment. 'Dry sex' is not popular in this area and increased lubrication was an important determinant of acceptability. Age, level of education and location did have some effect on preference. Although secrecy was a dominant theme in the FGDs, 87% of the women had informed their partners by the end of the trial. The products were generally well received. Female control was an important issue for both sexes. Male attitudes were ambivalent because female ownership of products increased women's control. Although they have clear preferences, women appear to accept the products generally and might use a single available product just as readily if choice was limited, as long as it conforms to general cultural preferences, such as those relating to wet/dry sex.
Adolescent↗
Fatty acid hydroperoxide lyase in tomato fruits: cloning and properties of a recombinant enzyme expressed in Escherichia coli.
Fatty acid hydroperoxide lyase (HPL) is a member of a novel subfamily of cytochrome P450 and catalyzes a cleavage reaction of fatty acid hydroperoxides to form short-chain aldehydes and oxo-acids. A cDNA encoding tomato fruit HPL (LeHPL) was obtained. An active LeHPL was expressed in E. coli and purified. It showed highest activity against the 13-hydroperoxide of linolenic acid, followed by that of linoleic acid. 9-Hydroperoxides were poor substrates. The absorption spectrum of the purified LeHPL in the native form was similar to that of most P450s although a CO-adduct having a lambda max at 450 nm could not be obtained. LeHPL activity is reversibly inhibited by nordihydroguaiaretic acid, while salicylic acid irreversibly inhibited it. LeHPL is kinetically inactivated by fatty acid hydroperoxides, especially 9-hydroperoxides. The inactivation is prevented by inhibitors of LeHPL. Thus, HPL catalytic activity is thought to be essential to its inactivation. During the inactivation, an abolition of the Soret band was evident, indicating that inactivation is caused mainly by degradation of the prosthetic heme in LeHPL.
Aldehyde-Lyases↗
Reflections from the field.
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Critical Illness↗
[Genetic factors involved in asthma and atopy. Studies in British families].
Both asthma and atopy run families indicating a strong genetic component. To investigate possible candidate gene regions, we have recruited 131 families without reference to atopy and asthma (random sample) and 60 extended families with two or more members affected by asthma (multiplex sample). Using both candidate and genome screen approaches, we have been able to provide evidence supporting the presence of candidate genes on chromosome 11q (E237G) and 12q but we have been unable to confirm reports of linkage and association for asthma on 5q. Our experience to date suggests that larger numbers of families are needed to increase the confidence of gene localisation and there is a need to improve the phenotypic description of asthma. Finally, it is essential that claims for linkage or association are confirmed in different populations using the same markers.
Asthma↗
Transcatheter closure of ventricular septal defects using the Rashkind device: initial experience.
We report our initial experience with transcatheter closure of ventricular septal defects (VSD) using the Rashkind device. Transcatheter closure of 25 VSDs was attempted in 16 patients with a median age of 2 (range 0.1-4) years and a median weight of 11 (range 4.1-19) kg. The location of the VSDs was apical in 14, midmuscular in 8, and anterior muscular in 3. Five patients had complex heart lesions, 10 patients had associated defects, including perimembranous VSD, atrial septal defect, patent ductus arteriosus, and coarctation of aorta. The remaining patient had isolated multiple muscular VSDs. The surgical repair of VSDs was a high-risk option in all the patients. Of the 25 attempted closures, 22 devices were placed successfully. Nine patients had a single device, four patients had two devices each and one patient had a total of five devices placed. In two patients attempts to close three VSDs were associated with major problems/death. Fourteen patients have been followed up for at least 1 year and all are doing well. Five patients, who otherwise remain asymptomatic, have a trace residual shunt. The fluoroscopy time ranged from 51 to 205 min (median 110) and the procedure time 120 to 300 min (median 200). The transcatheter closure of VSDs acts as a palliation as well as a definitive therapeutic modality in some patients with surgically inaccessible VSDs. Deployment of multiple devices in a patient is feasible. Increased experience may diminish the initial rate of complications.
Cardiac Catheterization↗
Enhancement of sterol synthesis by the monoterpene perillyl alcohol is unaffected by competitive 3-hydroxy-3-methylglutaryl-CoA reductase inhibition.
Monoterpenes such as limonene and perillyl alcohol (PA) are currently under investigation for their chemotherapeutic properties which have been tied to their ability to affect protein isoprenylation. Because PA affects the synthesis of isoprenoids, such as ubiquinone, and cholesterol is the end product of the synthetic pathway from which this isoprenoid pathway branches, we investigated the effects of this compound upon cholesterol metabolism in the colonic adenocarcinoma cell line SW480. PA (1 mM) inhibited incorporation of 14C-mevalonate into 21-26 kDa proteins by 25% in SW480 cells. Cholesterol (CH) biosynthesis was assessed by measuring the incorporation of 14C-acetate and 14C-mevalonate into 27-carbon-sterols. Cells treated with PA (1 mM) exhibited a fourfold increase in the incorporation of 14C-acetate but not 14C-mevalonate into cholesterol. Mevinolin (lovastatin), an inhibitor of 3-hydroxy-3-methylglutaryl-CoA(HMG-CoA) reductase, at 2 microM concentration, inhibited CH synthesis from 14C-acetate by 80%. Surprisingly, concurrent addition of mevinolin and PA did not significantly alter the stimulatory effects of PA. As observed differences in 14C-acetate and 14C-mevalonate precursor labeling could indicate PA affects early pathway events, the effects of this monoterpene on HMG-CoA reductase activity were evaluated. Unexpectedly, 1 mM PA did not stimulate activity of this enzyme. Consistent with its action as a reversibly bound inhibitor, in washed microsomes, 2 microM mevinolin pretreatment increased reductase protein expression causing a 12.7 (+/- 2.4)-fold compensatory HMG-CoA reductase activity increase; concurrent treatment with 1 mM PA attenuated this to a 5.3 (+/- 0.03)-fold increase. Gas chromatographic analysis confirmed CH was the major lipid present in the measured thin-layer chromatography spot. Since 14C-acetate incorporation into free fatty acid and phospholipid pools was not significantly affected by PA treatment, nonspecific changes in whole acetate pool sizes were not indicated. Because increases in endogenous CH synthesis should result in compensatory changes in exogenous sterol utilization, the effects of PA upon low density lipoprotein (LDL) receptor activity were evaluated. Consistent with the observed increases in CH synthesis, 1 mM PA decreased 125I-LDL internalization to 50% of the fetal bovine serum control; concurrent addition of 2 microM mevinolin attenuated this effect to a reduction of 80% of the control value. Data suggest that in certain colonic tumor cells PA strongly affects cholesterol metabolism via a mechanism of action that is insensitive to the HMG-CoA reductase inhibitor mevinolin.
Animals↗
Transcatheter closure of patent ductus arteriosus with the use of Rashkind occluders and/or Gianturco coils: long-term follow-up in 123 patients and special reference to comparison, residual shunts, complications, and technique.
BACKGROUND: This report describes the long-term follow-up of transcatheter closure of patent ductus arteriosus (PDA) with 2 different modalities in 123 patients of diverse ages. METHODS AND RESULTS: Between October 1990 and August 1997, 123 patients underwent transcatheter PDA (1.9 to 7.5 mm) closure at a mean age of 6.8 +/- 8.9 years (range 0.06 to 52) and mean weight of 20.9 +/- 17. 6 kg (range 2.7 to 83). In the initial procedure, the Rashkind device was used in 60, the Gianturco coil(s) in 60, and the Rashkind device with a coil in 3 patients. Six-month closure rate for the Rashkind group was 77% versus 90% for the coil group. The second procedure was carried out for residual shunt in 19 (14 in the Rashkind group and 5 in the coil group) and a third procedure in 1 patient from the Rashkind group. A balloon wedge catheter was used in 50 of 78 coil procedures to prevent coil embolization. One device and 11 coils (8 without balloon aid) embolized to the pulmonary arteries. The device and all coils except 2 were retrieved successfully. Overall, 122 (99%) patients showed complete PDA closure. The mean uneventful follow-up period was 44.11 +/- 23.77 months (range 8.7 to 90.28). CONCLUSIONS: Transcatheter closure of PDA is feasible in infants as well as in patients >50 years of age without significant complications. The coils are easy to implant, less expensive, and multiple coils may be used in moderately large (>3.5 mm) ducts more effectively than with the Rashkind device. The use of a balloon wedge catheter prevents immediate coil embolization. Multiple procedures are feasible and safe to achieve complete closure.
Adolescent↗
Twenty-four-hour access to emergency care for children in managed care.
Children's medical emergencies occur around the clock. In years past, the emergency department, open 24 hours a day, was a familiar site for treating these emergencies. However, in today's health care environment, the scenario can be more confusing. As many families move from a fee-for-service system into a managed care organization (MCO), they may be unclear about what they should do in an emergency involving their child. MCOs want to provide appropriate care, and at the same time, operate within a system designed to contain costs through the establishment of effective health care delivery systems. Providers of emergency services, including specialists in pediatric medicine and emergency medical services responders, also must contend with a different set of problems, including administrative entanglements and concerns about reimbursement for their services. This article continues the white paper series by the Emergency Medical Services for Children Managed Care Task Force.
Adolescent↗
R-(+)-perillyl alcohol-induced cell cycle changes, altered actin cytoskeleton, and decreased ras and p34(cdc2) expression in colonic adenocarcinoma SW480 cells.
Monoterpenes as S-(-)-perillyl alcohol (PA) have been shown to inhibit the isoprenylation of such growth regulatory proteins as ras. In this study, we investigated the effects of the R-(+) enantiomer of PA on cell cycle, signaling, and cytoskeletal control in the colonic adenocarcinoma cell line SW480, which carries a K-ras mutation. Cell cycle analysis by flow cytometry of SW480 cells treated with 1 mM PA for 24 hours demonstrated an increase in the number of cells in G0/G1 with a decrease in S phase, compared with untreated control cells. These cell cycle changes correlated with an inhibition of protein isoprenylation from (14)C-mevalonate and decreased expression of the cell cycle regulatory kinase p34(cdc2). Additionally, PA-treated cells acquired a flattened morphology with a condensation of cytoskeletal actin spikes to the periphery. This was in contrast to treatment with 15 microM mevinolin (MVN), a direct mevalonate synthesis inhibitor, which imparted to SW480 cells a more rounded and spindly morphology, associated with the depolymerization of actin microfilaments. Together, these data suggest that fluctuations in mevalonate and isoprenoid pools may involve different morphologic phenomenon. Because ras mediated signaling is related to the organization of the actin cytoskeleton, we investigated the effects of PA on the isoprenylation of ras. Although MVN treatment inhibited ras farnesylation, PA treatment decreased the expression of total ras protein. In summary, R-(+)-PA-induced cell signaling events correlated with alterations in the organization of cytoskeletal actin and decreased protein expression of growth regulatory proteins, such as ras and cdc2 kinase. These effects may contribute to the growth inhibitory activity of R-(+)-PA.
Journal Article↗
Hardy-Weinberg quality control.
An efficient test of deviation from Hardy-Weinberg frequencies with one degree of freedom was applied to 44 marker loci in a genome scan, and 7 loci had a significant excess of apparent homozygotes (chi2 (1) > 6) suggestive of typing error. In this example evidence for linkage did not increase when outliers were censored. Statistical quality control is an essential part of genotyping, and the effect of mistyping and map error should be considered in evaluating any genome scan.
Asthma↗
Energy balance during acute respiratory exacerbations in children with cystic fibrosis.
Acute respiratory exacerbations have been proposed to contribute to the negative energy balance which causes undernutrition in cystic fibrosis. However, no studies have measured their effect on all components of energy balance. The aim of this study was to measure the effect of an acute respiratory exacerbation on energy balance. Fourteen children (six females, eight males, mean+/-SD age 9.9+/-2.4 yrs) were studied when well and during the course of an acute respiratory exacerbation treated with intravenous antimicrobial therapy. The total energy expenditure was measured using the doubly-labelled water method, resting energy expenditure by ventilated hood indirect calorimetry, energy intake by household measures records, and fat malabsorption from measurements of dietary fat intake and faecal fat output. The exacerbation was associated with a significant reduction in energy intake (mean paired difference 47 kJ x kg of body weight(-1) x day(-1), p<0.01). Changes in fat malabsorption and resting energy expenditure were negligible. The absence of significant changes in body weight and composition, together with the trend towards lower total energy expenditure, suggested no marked negative energy balance during the exacerbation. In conclusion, treatment of acute respiratory exacerbation with intravenous antimicrobial therapy represents a relatively minor challenge to energy balance and nutritional status in children with cystic fibrosis.
Acute Disease↗