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Biomedical subjects

H Hughes

Publications and source records attributed to H Hughes.

At least 19 recordsLinked to original sources
PubMed2006

Randomized clinical trial comparing multiple stab incision phlebectomy and transilluminated powered phlebectomy for varicose veins.

BACKGROUND: The aim was to compare early postoperative subjective outcome measures in a randomized trial of multiple stab incision phlebectomy (MSIP) and transilluminated powered phlebectomy (TIPP) for the treatment of varicose veins. METHODS: Patients having surgery for varicose veins were randomized to receive either MSIP or TIPP for local avulsion of varicose veins. Operating time, number of incisions and postoperative outcome were analysed in both groups. Quality of life (QoL) was analysed before and 1 and 6 weeks after surgery using domain-specific (Burford pain scale), disease-specific (Aberdeen Varicose Vein Questionnaire) and generic (Short Form 36 and EuroQol 5D) instruments. RESULTS: Sixty-six patients consented to participate in the trial but four withdrew before surgery, so 33 patients underwent MSIP and 29 patients had TIPP. All patients had symptomatic or complicated varicose veins. There was no significant difference between groups in the total duration of surgery or the time taken for the avulsions. The number of incisions was significantly lower with TIPP. However, skin bruising at 1 and 6 weeks, and Burford pain score at 6 weeks were significantly higher in the TIPP group (P < 0.01 for bruising and P = 0.019 for pain). TIPP also had a greater adverse impact on generic QoL, resulting in a more prolonged recovery. CONCLUSION: TIPP had the advantage of fewer surgical incisions, but was associated with more extensive bruising, prolonged pain and reduced early postoperative QoL.

Adult↗
PubMed2005

Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome.

BACKGROUND: Sotos syndrome is characterised by learning difficulties, overgrowth, and a typical facial appearance. Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos. In contrast, a recurrent approximately 2 Mb microdeletion has been reported as responsible for approximately 50% of Japanese cases of Sotos. METHODS: We screened 471 cases for NSD1 mutations and deletions and identified 23 with 5q35 microdeletions. We investigated the deletion size, parent of origin, and mechanism of generation in these and a further 10 cases identified from published reports. We used "in silico" analyses to investigate whether repetitive elements that could generate microdeletions flank NSD1. RESULTS: Three repetitive elements flanking NSD1, designated REPcen, REPmid, and REPtel, were identified. Up to 18 cases may have the same sized deletion, but at least eight unique deletion sizes were identified, ranging from 0.4 to 5 Mb. In most instances, the microdeletion arose through interchromosomal rearrangements of the paternally inherited chromosome. CONCLUSIONS: Frequency, size, and mechanism of generation of 5q35 microdeletions differ between Japanese and non-Japanese cases of Sotos. Our microdeletions were identified from a large case series with a broad range of phenotypes, suggesting that sample selection variability is unlikely as a sole explanation for these differences and that variation in genomic architecture might be a contributory factor. Non-allelic homologous recombination between REPcen and REPtel may have generated up to 18 microdeletion cases in our series. However, at least 15 cannot be mediated by these repeats, including at least seven deletions of different sizes, implicating multiple mechanisms in the generation of 5q35 microdeletions.

Abnormalities, Multiple↗
PubMed2005

Adverse events and near miss reporting in the NHS.

OBJECTIVES: To conduct a multicentre study on adverse event and near miss reporting in the NHS and to explore the feasibility of creating a national system for collecting these data. DESIGN: Prospective voluntary reporting by staff with anonymised transfer of data was used by a national system to collect data from 18 NHS trusts. PARTICIPANTS: Staff from 12 acute trusts, three mental health trusts, two ambulance trusts, and one primary care trust. MAIN OUTCOMES MEASURED: Number of incidents, date and time of incident, patient age and sex, clinical speciality, location, outcome, risk rating, type and description of incident. RESULTS: A total of 28 998 incidents were reported including 11 766 (41%) slips, trips and falls, 2514 (9%) medication management incidents, 2429 (8%) resource issues, and 2164 (7%) treatment issues. 138 catastrophic and 260 major adverse outcomes were reported. Slips, trips and falls (n = 11 766) were the most common type of incident. CONCLUSIONS: Voluntary reporting by staff when linked to a multicentre data collecting system can yield information on a large number of incidents. This provides support for the principle of creating a national IT system to collect and analyse incident data.

Accidental Falls↗
PubMed2005

Venous thromboembolism associated with hip and knee replacement over a ten-year period: a population-based study.

This population-based study investigated the incidence and trends in venous thromboembolic disease after total hip and knee arthroplasty over a ten-year period. Death or readmission for venous thromboembolic disease up to two years after surgery for all patients in Scotland was the primary outcome. The incidence of venous thromboembolic disease, including fatal pulmonary embolism, three months after surgery was 2.27% for primary hip arthroplasty and 1.79% for total knee arthroplasty. The incidence of fatal pulmonary embolism within three months was 0.22% for total hip arthroplasty and 0.15% for total knee arthroplasty. The majority of events occurred after hospital discharge, with no apparent trend over the period. The data support current advice that prophylaxis should be continued for at least six weeks following surgery. Despite the increased use of policies for prophylaxis and earlier mobilisation, there has been no change in the incidence of venous thromboembolic disease.

Aged↗
PubMed2002

Vitreoretinopathy with phalangeal epiphyseal dysplasia, a type II collagenopathy resulting from a novel mutation in the C-propeptide region of the molecule.

A large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly was linked to COL2A1, the gene encoding proalpha1(II) collagen. Mutational analysis of the gene by exon sequencing identified a novel mutation in the C-propeptide region of the molecule. The glycine to aspartic acid change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype does not fit easily into pre-existing subgroups of the type II collagenopathies, which includes spondyloepiphyseal dysplasia, and the Kniest, Strudwick, and Stickler dysplasias.

Adult↗
PubMed2001

Parental mosaicism of JAG1 mutations in families with Alagille syndrome.

The Alagille syndrome (AGS), a congenital disorder affecting liver, heart, skeleton and eye in association with a typical face, is an autosomal dominant disease with nearly complete penetrance and variable expression. AGS is caused by mutations in the developmentally important JAG1 gene. In our mutation screening, where 61 mutations in JAG1 were detected, we identified five cases where mosaicism is present. Our results point to a significant frequency of mosaicism for JAG1 mutations in AGS of more than 8.2%. Because mosaicism may be associated with a very mild phenotype, the appropriate diagnosis of AGS and consequently the determination of the recurrence risk can be complicated.

Alagille Syndrome↗
PubMed2000

Human G protein gamma(11) and gamma(14) subtypes define a new functional subclass.

The mammalian gamma subunit family consists of a minimum of 12 members. Analysis of the amino acid sequence conservation suggests that the gamma subunit family can be divided into three distinct subclasses. The division of the gamma subunit family into these classes is based not only on amino acid homology, but also to some extent on functional similarities. In the present study, two new members of the gamma subunit family, the gamma(11) and gamma(14) subunits, are identified and characterized in terms of their expression and function. The gamma(11) and gamma(14) subunits are most closely related to the gamma(1) subunit and share similar biochemical properties, suggesting their inclusion in class I. However, despite their close phylogenetic relationship and similar biochemical properties, the gamma(1), gamma(11), and gamma(14) subunits exhibit very distinct expression patterns, suggesting that class I should be further subdivided and that the signaling functions of each subgroup are distinct. In this regard, the gamma(11) and gamma(14) subunits represent a new subgroup of farnesylated gamma subunits that are expressed outside the retina and have functions other than phototransduction.

Amino Acid Sequence↗
PubMed2000

Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.

Mutations in the methyl-CpG-binding protein gene MECP2 at Xq28 cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder characterized by a period of stagnation followed by regression in the development of young girls. Mutations were sought in MECP2 in 48 females with classical sporadic RTT, seven families with possible familial RTT and five sporadic females with features suggestive, but not diagnostic of RTT. Long distance PCR coupled with long-read direct sequencing was employed to sequence the entire MECP2 gene coding region in all cases. Mutations were identified in 44/55 (80%) unrelated classical sporadic and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT. Twenty-one different mutations were identified (12 missense, four nonsense and five frame-shift mutations); 14 of these were novel. All missense mutations were located either in the methyl-CpG-binding domain or in the transcription repression domain. Nine recurrent mutations were characterized in a total of 33 unrelated cases (73% of all cases with MECP2 mutations). Significantly milder disease was noted in patients carrying missense mutations as compared with those with truncating mutations ( P = 0. 0023), and milder disease was associated with late as compared with early truncating mutations ( P = 0.0190).

Amino Acid Sequence↗
PubMed2000

Fluoride in drinking water and risk of hip fracture in the UK: a case-control study.

BACKGROUND: Although the benefits of water fluoridation for dental health are widely accepted, concerns remain about possible adverse effects, particularly effects on bone. Several investigators have suggested increased rates of hip fracture in places with high concentrations of fluoride in drinking water, but this finding has not been consistent, possibly because of unrecognised confounding effects. METHODS: We did a case-control study of men and women aged 50 years and older from the English county of Cleveland, and compared patients with hip fracture with community controls. Current addresses were ascertained for all participants; for those who agreed to an interview and who passed a mental test, more detailed information was obtained about lifetime residential history and exposure to other known and suspected risk factors for hip fracture. Exposures to fluoride in water were estimated from the residential histories and from information provided by water suppliers. Analysis was by logistic regression. FINDINGS: 914 cases and 1196 controls were identified, of whom 514 and 527, respectively, were interviewed. Among those interviewed, hip fracture was strongly associated with low body-mass index (p for trend <0.001) and physical inactivity (p for trend <0.001). Estimated average lifetime exposure to fluoride in drinking water ranged from 0.15 to 1.79 ppm. Current residence in Hartlepool was a good indicator for high lifetime exposure to fluoride. After adjustment for potential confounders, the odds ratio associated with an average lifetime exposure to fluoride > or =0.9 ppm was 1.0 [95% CI 0.7-1.5]. INTERPRETATION: There is a low risk of hip fracture for people ingesting fluoride in drinking water at concentrations of about 1 ppm. This low risk should not be a reason for withholding fluoridation of water supplies.

Aged↗
PubMed2000

Glutaraldehyde-induced cross-links: a study of model compounds and commercial bioprosthetic valves.

BACKGROUND AND AIM OF THE STUDY: The treatment of bioprosthetic tissue routinely involves the use of glutaraldehyde, although the specific chemistry of glutaraldehyde fixation is not fully understood. Descriptions of definitive work on this reaction using model compounds are limited. The aim of the present study was to increase our understanding of the chemistry involved in the treatment of collagen-rich tissue with glutaraldehyde. Initially, 6-aminohexanoic acid (6-AHA) was used to model the lysine/hydroxylysine molecules in collagen before studying the more complex chemistry of the tissue. METHODS: The reaction between 0.6% glutaraldehyde and 6-AHA was studied by positive ion electrospray-mass spectroscopy. Untreated, locally treated and commercially produced explanted and non-implanted tissue were hydrolyzed under various conditions and analyzed both directly and after derivatization with 4-chlorophenylhydrazine, 4-bromophenacyl bromide and dansyl chloride by reverse-phase-high performance liquid chromatography-mass spectrometry. RESULTS: The mass spectral data obtained from the reaction of glutaraldehyde with 6-AHA showed the presence of alpha,beta unsaturated aldehydes and their further condensation products involving Michael reactions of glutaraldehyde, Schiff base cross-links and various cyclization products incorporating pyridinium and dihydropyridine ring structures. The only stable cross-link detected was an 'anabilysine'-like compound. Similar structures were present in the tissue, and anabilysine was identified by tandem mass spectrometry. CONCLUSION: The results from the reaction of glutaraldehyde with 6-AHA agree with those published previously. The only detectable stable cross-link definitively identified in treated bioprosthetic tissue was anabilysine. No long-chain polymers of glutaraldehyde were detected.

Aminocaproic Acid↗
PubMed2000

In vivo metabolism and mass balance of 4-[4-fluorophenoxy]benzaldehyde semicarbazone in rats.

The pharmacokinetics, mass balance, tissue distribution, and metabolism of Co 102862 was investigated in rats after a single oral dose. [(14)C]Co 102862 showed multiexponential pharmacokinetics in rat plasma with an extensive distribution phase. After p.o. administration (approximately 10 mg/kg), the half-lives were long for total radioactivity compared with unchanged Co 102862. Profiles of rat urine and bile suggest that Co 102862 is extensively metabolized in vivo. [(14)C]Co 102862 was extensively distributed into all tissues, with the fatty tissues and secretory glands tissues containing the highest radioactivity. Elimination of radioactivity from the tissues had an estimated half-life of 14 days. A total of 91% of the administered radioactivity was recovered in both intact and bile-duct cannulated rats over 120 and 48 h, respectively, with the majority ( approximately 74%) of the radioactivity being excreted in the urine. Approximately 10% of the total radioactivity remained in the tissues on day 5 and decreased with time to approximately 3% on day 28. Bile-duct cannulated experiments show the enterohepatic circulation is an important route of elimination and reabsorption. Six metabolites were identified in the urine and bile of which the carboxylic acid was the major metabolite. The carboxylic acid was the only metabolite found in plasma and was probably responsible for the radioactivity in the tissues.

Administration, Oral↗
PubMed1998

Palmitoyl derivatives of interferon alpha: potential for cutaneous delivery.

Palmitoyl derivatives of interferon alpha2b (p-IFNalpha) were prepared by covalent attachment of the fatty acid to lysine residues in the protein through a reaction with N-hydroxysuccinimide palmitate ester. The p-IFNalpha was characterized by capillary electrophoresis (CE), mass spectrometry (MS), SDS-PAGE, and antiviral assay. Flow-through diffusion cells and human breast skins were used to measure cutaneous and percutaneous absorption. Formation of p-IFNalpha derivatives was demonstrated by CE to be dependent on reaction time and reagent: protein ratio. Electrospray MS of the crude p-IFNalpha mixture indicated three populations of IFNalpha derivatives with 10, 11, and 12 palmitoyl substitutions. The addition of palmitoyl residues to IFNalpha under the conditions described reduced the antiviral specific activity by 50%. However, the cutaneous absorption of p-IFNalpha was about 5-6 times greater than the parent protein. The amount of p-IFNalpha and IFN alpha in whole skin after 24 h of treatment was 2.106 +/- 1.216 microg/cm2 and 0.407 +/- 0.108 microg/cm2, respectively. Approximately two times higher flux was detected for p-IFNalpha compared to the nonfatty acylated IFNalpha. The total amount of drug diffused in 24 h was also approximately two times higher for the p-IFNalpha. The results indicate a potential for using fatty acylated derivatives of IFN alpha for dermal and transdermal delivery.

Acylation↗
PubMed1997

Abnormalities of copper accumulation in cell lines established from nine different alleles of mottled are the same as those found in Menkes disease.

Menkes disease (MD) is caused by a defect in copper homeostasis and has a recognised mouse model, mottled (Atp7aMo). Copper uptake and retention assays performed on fibroblast cultures have been used successfully for pre- and postnatal diagnosis of Menkes disease. We report here the results of these assays applied to primary fibroblast cultures established from nine independent mottled alleles associated with phenotypes of varying severity maintained on identical genetic backgrounds. No significant differences were found between the different alleles, or between the mottled cultures and fibroblasts established from MD patients. Thus, in the mouse, the data obtained for copper retention/uptake at the cellular level do not correlate with the severity of the phenotype.

Adenosine Triphosphatases↗
PubMed1996

Formaldehyde replaces glutaraldehyde in porcine bioprosthetic heart valves.

BACKGROUND AND AIMS OF THE STUDY: In the production of porcine bioprostheses, the initial glutaraldehyde treatment is often followed by a short incubation in formaldehyde to ensure sterility of the valve. It is assumed that the glutaraldehyde cross links are stable and that the formaldehyde step does not alter the glutaraldehyde incorporated. The objective of this study was to determine whether the formaldehyde interacts with the tissue to cause changes in the glutaraldehyde composition. MATERIALS AND METHODS: Two methods of tissue treatment were investigated: (i) fresh porcine leaflet tissue was treated with glutaraldehyde, followed by storage in formaldehyde, (ii) tissue processed in glutaraldehyde and transferred to formaldehyde for six hours was returned to glutaraldehyde for storage. The content of the two aldehydes was estimated by high performance liquid chromatography (HPLC), using an adaptation of the method developed by Hughes et al, which measures the acid labile Schiff bases formed between the collagen and the aldehyde. RESULTS: The initial content of glutaraldehyde in the tissue declined from 63 +/- 10 nmol/mg dry weight to 21 +/- 4 nmol/mg dry weight when the leaflets were placed in formaldehyde for 24 hours. The initial uptake of formaldehyde was 800 +/- 144 nmol/mg dry weight after 24 hours and this declined to 370 +/- 33 nmol/mg dry weight over a 16 week period of storage in formaldehyde. By this stage, the level of glutaraldehyde had decreased to 2.4 +/- 0.2 nmol/mg dry weight. There was a sharp decline in the glutaraldehyde concentration from 89 +/- 6 nmol/mg dry weight to 14 +/- 1 nmol/mg dry weight when the tissue was placed in 4% formaldehyde solution for six hours. The formaldehyde uptake was 770 +/- 54 nmol/mg dry weight. After return to 0.625% glutaraldehyde solution the formaldehyde concentration declined whilst the glutaraldehyde concentration initially increased. CONCLUSIONS: These results show that the formaldehyde reacts with the epsilon amino groups of lysine which had not reacted with glutaraldehyde, probably for steric reasons; and that formaldehyde replaces some glutaraldehyde in the tissue by a mass action effect. The tissue concentration of both aldehydes subsequently declined over the study period.

Animals↗