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Biomedical subjects

P J Hughes

Publications and source records attributed to P J Hughes.

At least 19 recordsLinked to original sources
PubMed2005

Botulinum toxin injection in the treatment of tennis elbow. A double-blind, randomized, controlled, pilot study.

BACKGROUND: A recent report has suggested that local injection of botulinum toxin type A is an effective method of treatment for chronic tennis elbow. The toxin is thought to provide temporary paralysis of the painful common extensor origin, thereby allowing a healing response to occur. To test this theory, we performed a double-blind, randomized, controlled, pilot trial comparing injections of botulinum toxin type A with those of a placebo (normal saline solution) in the treatment of chronic tennis elbow. METHODS: Forty patients with a history of chronic tennis elbow for which all conservative treatment measures, including steroid injection, had failed were randomized into two groups. Half the patients received 50 units of botulinum toxin type A, and the remainder received normal saline solution. The intramuscular injections were performed 5 cm distal to the maximum point of tenderness at the lateral epicondyle, in line with the middle of the wrist. The two solutions used for the injections were identical in appearance and temperature. The results of a quality-of-life assessment with the Short Form-12 (SF-12), the pain score on a visual analogue scale, and the grip strength measured with a validated Jamar dynamometer were recorded before and three months after the injection. RESULTS: Three months following the injections, there was no significant difference between the two groups with regard to grip strength, pain, or quality of life. CONCLUSIONS: With the numbers studied, we failed to find a significant difference between the two groups; thus, we have no evidence of a benefit from botulinum toxin injection in the treatment of chronic tennis elbow.

Botulinum Toxins, Type A↗
PubMed2004

Phytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatment.

We investigated the ability of 37 flavonoids and flavonoid sulfoconjugates, including some abundant dietary constituents, to act as substrates and/or inhibitors of the sulfotransferase and sulfatase enzymes that interconvert active estrogens and inactive estrogen sulfates in human tissues. The enzymes studied include estrogen sulfotransferase, the thermostable phenolsulfotransferase that acts on a range of substrates including estrogens; steroid sulfatase; and two related enzymes, monoamine phenolsulfotransferase and arylsulfatase A. Several dietary flavonoids, including the soy isoflavones genistein and daidzein, were sulfated by these human sulfotransferases. Many flavonoids were potent inhibitors of thermostable phenolsulfotransferase. Genistein and equol were potent mixed inhibitors of hepatic estrogen sulfotransferase, with inhibitory constant values of 500 nM and 400 nM, respectively. Monoamine phenolsulfotransferase activity was relatively unaffected by flavonoids, but this enzyme was mainly responsible for the sulfation of flavonoids at concentrations greater than 1 micro M. Of the compounds tested, only daidzein 4,7-bisulfate, a trace metabolite in humans, significantly inhibited steroid sulfatase in the micromolar concentration range. Hence, dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues.

Arylsulfotransferase↗
PubMed2003

Boundary conditions at the tendon-bone interface.

The reconstruction of a tendon-bone interface, as in rotator-cuff repairs, remains a challenging surgical problem. There is however, little data to show what effect joint position or repair loading under physiological conditions have on the repaired tendon-bone interface. A change in the amount of contact area or load at the tendon-bone interface may influence healing. In this study we investigated the effect of limb position and boundary conditions on the tendon-bone interface in an in vitro rabbit tendon-bone repair model using both unlinked and linked suture repairs.

Animals↗
PubMed2001

Up-regulation of steroid sulphatase activity in HL60 promyelocytic cells by retinoids and 1alpha,25-dihydroxyvitamin D3.

HL60 promyeloid cells express both classes of oestrogen receptor (ERalpha and ERbeta). We show that hydrolysis of oestrone sulphate by steroid sulphatase is a major source of oestrone in HL60 cells, and that most of the released oestrone is not metabolized further to 17beta-oestradiol. Treatment of HL60 cells with retinoids or 1alpha,25-dihydroxyvitamin D3 increased steroid sulphatase mRNA and activity in parallel with the induction of CD11b, an early marker of myeloid differentiation that is expressed before the differentiating cells stop proliferating. Use of agonists and antagonists against retinoid receptor-alpha and retinoid receptor-X revealed that both classes of retinoid receptor can drive steroid sulphatase up-regulation. Steroid sulphatase activity fluctuates during the cell cycle, being highest around the transition from G1 to S phase. During the differentiation of HL60 cells induced by all-trans-retinoic acid or 1alpha,25-dihydroxyvitamin D3, there is increased conversion of 17beta-oestradiol into oestrone by an oxidative 17beta-hydroxysteroid dehydrogenase. Treatment of Caco-2 colon adenocarcinoma cells with all-trans-retinoic acid or 1alpha,25-dihydroxyvitamin D3 also increases 17beta-oestradiol oxidation to oestrone. An increase in local oestrone production therefore occurs in multiple cell types following treatment with retinoids and 1alpha,25-dihydroxyvitamin D3. The possible involvement of locally produced oestrogenic steroids in regulating the proliferation and differentiation of myeloid cells is discussed.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Acute transverse myelitis and Guillain-Barré overlap syndrome with serological evidence for mumps viraemia.

Both acute transverse myelitis (ATM) and Guillain-Barré syndrome (GBS) occur as rare associations with mumps viraemia but to our knowledge, concurrent ATM and GBS related to mumps has only been reported once previously. We describe the case of a young woman presenting with confusion and collapse 2 weeks after a flu-like illness. An initial diagnosis of transverse myelitis was made on the basis of the clinical findings and radiological evidence of a swollen spinal cord with uniform high signal change on T2 weighted MRI. The patient was treated with intravenous methylprednisolone without significant recovery. The diagnosis was later revised to include GBS on the basis of worsening facial diplegia in the setting of a flaccid tetraparesis, and neurophysiological evidence of a sensorimotor axonal polyradiculoneuropathy. Acute mumps viraemia was confirmed on serological grounds. The patient made an improvement in ventilatory capacity with intravenous immunoglobulin treatment.

Adult↗
PubMed2001

Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens?

Phytoestrogens are natural constituents of our diets that have been suggested to protect against hormone-dependent breast cancer. Some of the diverse effects of these compounds may be attributed to ligand-dependent differences in their interaction with oestrogen receptor sub-classes. However, phytoestrogens can also inhibit enzymes that are involved in the generation and removal of endogenous steroid hormones. Among the most potent effects of dietary phytoestrogens is their ability to inhibit the sulphotransferases that sulphate both oestrogenic steroids and a variety of environmental chemicals, including dietary pro-carcinogens. Circulating steroid sulphates are thought to be the major source of oestradiol in post-menopausal breast tumours and sulphation is a key step in the activation of some dietary pro-carcinogens. Hence the inhibition of sulphotransferases by dietary phytoestrogens may have complex effects upon human susceptibility to breast cancer.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Arginine-glycine-aspartic acid motif is critical for human parechovirus 1 entry.

The human parechovirus 1 RGD motif in VP1 was studied by mutagenesis. An RGD-to-RGE change gave only revertant viruses with a restored RGD, while deletion of GD was lethal and nonrevertable. Mutations at the +1 and +2 positions had some effect on growth properties and a +1 M-to-P change was lethal. These studies indicate that the RGD motif plays a critical role in infectivity, presumably by interacting with integrins, and that downstream amino acids can have an influence on function.

Amino Acid Sequence↗
PubMed2000

Estrogenic alkylphenols induce cell death by inhibiting testis endoplasmic reticulum Ca(2+) pumps.

Industrial alkylphenols in the environment may act as "xenoestrogens" to disrupt testicular development and decrease male fertility. Amongst possible targets for these compounds are testicular Sertoli cells, which nurture the developing sperm cells. We demonstrate that SERCA 2 and 3 Ca(2+) pumps are relatively abundant in rat testis microsomal membranes, and also in Sertoli, myoid, and TM4 cells (a Sertoli cell line). A number of estrogenic alkylphenols such as nonylphenol, octylphenol, bisphenol A, and butylated hydroxytoluene all inhibit testicular Ca(2+) ATPase in the low micromolar concentration range. These agents also mobilize intracellular Ca(2+) in intact TM4 cells in a manner consistent with the inhibition of ER Ca(2+) pumps. Alkylphenols dramatically decrease the viability of TM4 cells, an effect that is reversed by either a caspase inhibitor or by BAPTA, and is therefore consistent with Ca(2+)-dependent cell death via apoptosis. We postulate that alkylphenols disrupt testicular development by inhibiting ER Ca(2+) pumps, thus disturbing testicular Ca(2+) homeostasis.

Animals↗
PubMed2000

Sulfation of "estrogenic" alkylphenols and 17beta-estradiol by human platelet phenol sulfotransferases.

We have investigated the ability of alkylphenols to act as substrates and/or inhibitors of phenol sulfotransferase enzymes in human platelet cytosolic fractions. Our results indicate: (i) straight chain alkylphenols do not interact with the monoamine-sulfating phenol sulfotransferase (SULT1A3); (ii) short chain 4-n-alkylphenols (C < 8) are substrates for the phenol-sulfating enzymes (SULT1A1/2), which exhibit two activity maxima against substrates with alkyl chain lengths of C1-2 and C4-5; (iii) long chain 4-n-substituted alkylphenols (C >/= 8) are poor substrates and act as inhibitors of SULT1A1/2; (iv) human platelets contain two activities, of low and high affinity, capable of sulfating 17beta-estradiol, and 4-n-nonylphenol is a partial mixed inhibitor of the low affinity form of this activity. We conclude that by acting either as substrates or inhibitors of SULT1A1/2, alkylphenols may influence the sulfation, and hence the excretion, of estrogens and other phenol sulfotransferase substrates in humans.

Alkanes↗
PubMed2000

Dysphagia in treated nasopharyngeal cancer.

OBJECTIVES: To investigate the prevalence of long-term dysphagia in patients treated for nasopharyngeal carcinoma (NPC) by radiotherapy. Study Design Questionnaire-based assessment, clinical examination, and videofluoroscopic assessment of 50 patients, ages 26 to 75 years (average, 49 years), treated for NPC 12 to 119 months (average, 56 months) previously with no evidence of disease recurrence. METHODS: Administered questionnaire assessment of patients eating and swallowing. Clinical examination by a single experienced clinician. Videofluoroscopy was used to record swallowing of solid, paste, and liquid bolus. Pharyngeal transit time (PTT) was recorded, and the video recordings were assessed by two experienced observers for abnormalities. RESULTS: Fifty patients completed the questionnaire and were examined. Seventy-six percent reported dysphagia, 97% had xerostomia, and 78% had no gag reflex. Forty-nine patients underwent videofluoroscopy. Abnormal pharyngeal contraction was observed on videofluoroscopy in 93% of the subjects. Silent aspiration was observed in 22% of the patients. PTT was prolonged from a normal of 1 second to 1.9 seconds for solid, 1.7 seconds for paste, and 1.3 seconds for liquid consistencies. CONCLUSIONS: Subjective and objective swallowing abnormalities are common after radiotherapy for NPC. The implications of this finding and possible causes are discussed.

Adult↗
PubMed2000

A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) characteristically causes severe or fatal muscle weakness in male infants. Mutations in the gene MTM1, encoding the protein myotubularin, can be identified in most families. Prior to this report, XLMTM was thought not to cause symptomatic manifestations in female carriers. We describe an adult female from a large family with typical XLMTM. The patient had progressive disabling muscle weakness of later onset and lesser severity than that observed in affected males. The distribution of weakness resembled typical XLMTM with facial weakness, marked limb-girdle weakness, respiratory muscle involvement and dysphagia. Analysis of the MTM1 gene identified a heterozygous missense mutation (G378R) within the highly conserved tyrosine phosphatase site of myotubularin. We did not identify significantly skewed X-inactivation. We conclude that XLMTM is capable of causing significant disability in heterozygotes.

Female↗
PubMed2000

The 2A proteins of three diverse picornaviruses are related to each other and to the H-rev107 family of proteins involved in the control of cell proliferation.

The 2A protein appears to be diverse among picornaviruses, in contrast to the other non-structural proteins, which have homologous structures and functions. In enteroviruses and rhinoviruses, 2A is a trypsin-like protease involved in protein processing and in shut-off of host-cell macromolecular synthesis. The aphthovirus and cardiovirus 2A is associated with an unusual processing event at the 2A/2B junction. It is shown here that the 2A protein of several diverse picornaviruses, the human parechoviruses, Aichi virus and avian encephalomyelitis virus, possess previously unrecognized conserved motifs and are likely to have a common function. Moreover, these motifs, a conserved histidine and flanking amino acids, an asparagine-cysteine dipeptide and a putative transmembrane domain, are characteristic of a family of cellular proteins, at least two of which are involved in the control of cell growth. These observations have important implications for an understanding of picornavirus genome structure and evolution, as well as pointing to possible functions of 2A in these viruses.

Amino Acid Sequence↗
PubMed2000

In vivo and in vitro identification of structural and sequence elements of the human parechovirus 5' untranslated region required for internal initiation.

Sequence analysis of the picornavirus echovirus 22 led to its classification as the first member of a new genus, Parechovirus, and renaming as human parechovirus type 1 (HPeV1). Although distinct from other genera in most of the genome, the 5' untranslated region (5'UTR) shows similarities to that of cardio/aphthoviruses in some of its structural domains (A to L). The 5'UTR plays an important role in picornavirus translation initiation and in RNA synthesis. To investigate translation in HPeV1, we engineered an extensive range of mutations (including precise deletions and point mutations) into the 5'UTR. Their effects were studied both by in vitro transcription-translation using a bicistronic construct and by in vivo studies using an infectious, full-length HPeV1 cDNA. These approaches allowed the HPeV1 internal ribosome entry site (IRES) to be mapped. Deletions within the first 298 nucleotides had little impact in the in vitro system, while deletions of nucleotides 298 to 538 had a significant effect. Precise removal of domains H and L (nucleotides 287 to 316 and 664 to 682, respectively) did not significantly reduce translation efficiency in vitro, while domains I, J, and K (nucleotides 327 to 545, 551 to 661, and 614 to 645, respectively) appeared to have much more important roles. Mutation of a phylogenetically conserved GNRA motif (positions 421 to 424) within domain I severely reduced translation. We also confirmed the identity of the AUG (positions 710 to 712) which initiates the open reading frame, the positive identification of which has not been possible previously, as the N terminus of the polyprotein is blocked and not amenable to sequence analysis. This is therefore important in understanding parechovirus genome organization. Mutation of the AUG or an upstream polypyrimidine tract leads to aberrant translation, suggesting they both form part of the parechovirus Yn-Xm-AUG motif. In vivo experiments confirmed the importance of domains I, J, and K, the conserved GNRA motif, polypyrimidine sequences, and AUG, as mutations here were lethal. These features are also important in the IRES elements of cardio/aphthoviruses, but other features reported to be part of the IRES of some members of these genera, notably domains H and L, do not appear to be critical in HPeV1. This adds weight to the idea that there may be functional differences between the IRES elements of different picornaviruses, even when they share significant structural similarity.

5' Untranslated Regions↗
PubMed2000

Internal carotid artery occlusion following sports diving.

A case of internal carotid artery occlusion following a sports dive is described. The investigation and management of this condition is discussed with particular reference to blunt trauma being a risk factor for carotid artery occlusion.

Adult↗
PubMed1998

Inositol hexakisphosphate in Schizosaccharomyces pombe: synthesis from Ins(1,4,5)P3 and osmotic regulation.

Schizosaccharomyces pombe extracts synthesize InsP6 (myo-inositol hexaphosphate) from Ins(1,4,5)P3 plus ATP. An S. pombe soluble fraction converts Ins(1,4,5)P3 into Ins(1,4,5,6)P4 and Ins(1,3,4, 5)P4, in a constant ratio of approximately 5:1, and thence to Ins(1, 3,4,5,6)P5 and InsP6. We have purified a soluble Mg2+-dependent kinase of molecular mass approximately 41 kDa that makes Ins(1,4,5, 6)P4 and Ins(1,3,4,5)P4 in the same ratio and also converts Ins(1,4, 5,6)P4 or Ins(1,3,4,5)P4 into Ins(1,3,4,5,6)P5 and InsP6. Of InsP3 isomers other than Ins(1,4,5)P3, only the non-biological molecule Ins(1,4,6)P3 potently 'competed' with all steps in conversion of Ins(1,4,5)P3 into InsP6. Examination of molecular graphics representations allowed us to draw tentative conclusions about the environment needed for an hydroxyl group to be phosphorylated by this kinase and to predict successfully that the purified kinase would phosphorylate the 5-hydroxyl of Ins(1,4,6)P3. S. pombe that have been cultured with [3H]inositol contains a variety of 3H-labelled inositol polyphosphates, with Ins(1,4,5)P3 and InsP6 the most prominent, and the InsP6 concentration quickly increases in hyper-osmotically stressed S. pombe. This yeast therefore contains InsP6 and Ins(1,4,5)P3 as normal constituents, makes more InsP6 when hyper-osmotically stressed and contains a versatile inositol polyphosphate kinase that synthesizes InsP6 from Ins(1,4,5)P3.

Homeostasis↗
PubMed1998

Ionophore residues in eggs in Northern Ireland: incidence and cause.

Monensin, salinomycin and narasin were detectable in six, two and one, respectively, out of 161 eggs surveyed in Northern Ireland in 1994. In all cases, the concentrations detected were less than 2.5 ng/g. Lasalocid was detectable in 107 eggs at concentrations ranging from 0.3 to 129 ng/g. Cross-contamination of unmedicated feeds with monensin during feed manufacture (up to eight batches of unmedicated feed contaminated with monensin) was similar to that previously observed for lasalocid (up to nine batches contaminated). Therefore differences in the incidence in eggs could not be explained by differential carry-over during feed manufacture. In a feeding trial it was shown that the relative ability of monensin, salinomycin and lasalocid to accumulate in eggs was in the ratio 0.12:3.3:63 ng/g egg per mg/kg feed, respectively. This indicated that the potential for monensin and salinomycin to cause residues in eggs was very low, by comparison with lasalocid. In 1995, a granular formulation of the lasalocid premix was introduced into the United Kingdom that decreased the carry-over of this drug from medicated to unmedicated feed. Six months after the introduction of this formulation, the incidence of lasalocid residues in eggs (21%) was lower than that found (66.5%) in an earlier survey (1994) carried out, and published, by this laboratory.

Animal Feed↗
PubMed1998

Molecular analysis of human parechovirus type 2 (formerly echovirus 23).

Picornaviruses have been divided into five genera until recently, when a sixth genus, Parechovirus, was defined. Human parechovirus type 1 (HPeV1; formerly echovirus 22) was the first recognized member of this genus and preliminary sequence analysis of echovirus 23 [now renamed human parechovirus type 2 (HPeV2)] suggested that it is also a parechovirus. Here we describe the complete nucleotide and predicted amino acid sequences of HPeV2, which indicate a close relationship to HPeV1 throughout the genome. Sequence covariance in the 5' untranslated region allows a prediction of the secondary structure, which indicates that these parechoviruses have a type 2 internal ribosome entry site, most closely related to that of cardioviruses. Overall, HPeV2 has 87.9% amino acid identity with HPeV1, most divergence being seen in regions of the capsid proteins that probably define antigenic sites. The N-terminal sequence extension to VP3, seen only in parechoviruses, is highly basic in both viruses, but has a variable sequence, suggesting that it does not have a sequence-specific role. There is an RGD motif near the C terminus of VP1, in an analogous location to that in HPeV1 which is believed to be functionally significant. The results confirm that both viruses are parechoviruses and give insights into the molecular features of this genus.

Amino Acid Sequence↗