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Biomedical subjects

W Hughes

Publications and source records attributed to W Hughes.

At least 19 recordsLinked to original sources
PubMed2004

Cryoprecipitate prepared from plasma treated with methylene blue plus light: increasing the fibrinogen concentration.

When cryoprecipitate is prepared from plasma which has been treated with methylene blue plus light (MB) for the purpose of virus inactivation, clottable fibrinogen content is 40% lower compared with units prepared from untreated plasma. Initial studies showed that when frozen MB plasma units were removed to +2 to +6 degrees C for 4 h and then returned to -40 degrees C prior to cryoprecipitation, fibrinogen recoveries increased from 24 to 42%. Although fibrinogen yield improved when plasma units were stored at +2 to +6 degrees C for varying lengths of time, FVIII levels decreased with increasing time. Conditioning for 8 h was studied in more detail. Groups of two plasma units were mixed together, divided into two equal units, frozen/thawed and treated with MB. One of each pair was stored continually at -40 degrees C, whereas the other was removed to +2 to +6 degrees C for 8 h. Samples were assayed for fibrinogen, FVIII, VWF:Ristocetin cofactor activity (RCo), VWF:Ag and VWF:Collagen binding (CB). The cryoprecipitate fibrinogen content increased to a mean of 207 mg unit(-1). VWF:Ag, VWF:RCo and VWF:CB recoveries also increased. FVIII recovery decreased from 50 to 45% (mean 124 iu unit(-1)). Conditioning has been validated for routine production of cryoprecipitate from imported plasma.

Blood Coagulation↗
PubMed2001

The effect of atovaquone on etoposide pharmacokinetics in children with acute lymphoblastic leukemia.

PURPOSE: The use of trimethoprim/sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia in patients with acute lymphoblastic leukemia (ALL) may cause undesirable adverse effects: fungal overgrowth, neutropenia, and drug resistance. A possible alternative is atovaquone, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity. However, it is not known if atovaquone alters the disposition or adverse effects of antileukemic drugs. METHODS: Using a crossover study design, we compared the pharmacokinetics of etoposide and its CYP3A4-formed catechol metabolite when given as a 300 mg/m2 i.v. infusion following daily atovaquone versus trimethoprim/sulfamethoxazole in nine patients. RESULTS: The area under the concentration time curve (AUC) of etoposide, etoposide catechol and the catechol to etoposide AUC ratio were slightly higher (a median of 8.6%, 28.4%, and 25.9%) following atovaquone as compared to trimethoprim/sulfamethoxazole (P=0.055, P= 0.031 and P=0.023), respectively. In vitro analysis in human liver microsomes showed modest inhibition of etoposide catechol formation in the presence of atovaquone. Using uptake of 3H-vinblastine in L-MDR1 cells, atovaquone was shown to inhibit P-glycoprotein with an apparent Ki of 95.6 microM. CONCLUSIONS: Although the effect of atovaquone on etoposide disposition was modest, in light of the fact that the risk of etoposide-related secondary acute myeloid leukemia has been linked to minor changes in schedule and concurrent therapy, we suggest caution with the simultaneous administration of atovaquone and etoposide, particularly if used with other CYP3A4/P-glycoprotein substrates.

Adolescent↗
PubMed2001

Haplotype tagging for the identification of common disease genes.

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

Base Sequence↗
PubMed1999

Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children.

Abacavir (formerly 1592U89) is a potent 2'-deoxyguanosine analog reverse transcriptase inhibitor that has been demonstrated to have a favorable safety profile in initial clinical trials with adults with human immunodeficiency virus (HIV) type 1 infection. A phase I study was conducted to evaluate the pharmacokinetics and safety of abacavir following the administration of two single oral doses (4 and 8 mg/kg of body weight) to 22 HIV-infected children ages 3 months to 13 years. Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma abacavir concentrations were determined by high-performance liquid chromatography, and data were analyzed by noncompartmental methods. Abacavir was well tolerated by all subjects. The single abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was rapidly absorbed, with the time to the peak concentration in plasma occurring within 1.5 h postdosing. Pharmacokinetic parameter estimates were comparable among the different age groups for each dose level. The mean maximum concentration in plasma (Cmax) and the mean area under the curve from time zero to infinity (AUC0-infinity) increased by 16 and 45% more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (Cmax increased from 1.69 to 3.94 micrograms/ml, and AUC0-infinity increased from 2.82 to 8.09 micrograms.h/ml). Abacavir was rapidly eliminated, with a mean elimination half-life of 0.98 to 1.13 h. The mean apparent clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the dose increased. Neither body surface area nor creatinine clearance were correlated with pharmacokinetic estimates at either dose. The extent of exposure to abacavir appears to be slightly lower in children than in adults, with the comparable unit doses being based on body weight. In conclusion, this study showed that abacavir is safe and well tolerated in children when it is administered as a single oral dose of 4 or 8 mg/kg.

Adolescent↗
PubMed1998

Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children. Pediatric AIDS Clinical Trials Group.

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.

AIDS-Related Opportunistic Infections↗
PubMed1997

Secondary structure and shape of plasma sex steroid-binding protein--comparison with domain G of laminin results in a structural model of plasma sex steroid-binding protein.

We have analyzed the secondary structure, shape and dimensions of plasma sex steroid-binding protein (SBP) by CD, size-exclusion chromatography and electron microscopy. CD spectra show extrema at 186 nm and 216 nm characteristic for beta-sheet structures. Analysis with different algorithms indicates 15% alpha-helix, 43% beta-sheet and 10-16% beta-turn structures. An irreversible structural change is observed upon heating above 60 degrees C, which correlates with the loss of steroid-binding activity. As the SBP sequence shows similarity with domains of several multidomain proteins, including laminins, we evaluated the structure of domain G of laminin-1. The CD spectrum shows extrema at 200 nm and 216 nm. Deconvolution results in 13% alpha-helix, 32% beta-sheet and 15% beta-turn structures. Steroid-binding assays indicate that laminin and fragments thereof have no activity. Size-exclusion chromatography reveals that SBP has an extended shape and can be modeled as a cylinder with a length and diameter of 23 nm and 3 nm, respectively. This shape and the dimensions are in agreement with the appearance on electron micrographs. We propose a model for the structure of SBP in which two monomers assemble head to head with the steroid-binding site located in the center of the rod-like particle.

Amino Acid Sequence↗
PubMed1996

Direct evidence for the localization of the steroid-binding site of the plasma sex steroid-binding protein (SBP or SHBG) at the interface between the subunits.

Complete dissociation of dimeric plasma sex steroid-binding protein (SBP or SHBG) was obtained in 6 M urea at 10 degrees C. Removal of urea resulted in the refolding of monomers, followed by reformation of dimeric SBP, which migrates with the same mobility as the native protein. Dimerization does not require Ca+2 or steroid. Renatured monomers yield dimers with dissociation constants for 5 alpha-dihydrotesterone (DHT) and 17 beta-estradiol (E2) indistinguishable from those of native human SBP. This phenomenon was also demonstrated by mixing human and rabbit SBPs that, upon renaturation, form a hybrid dimer composed of one human subunit and one rabbit subunit. The hybrid binds both DHT and E2 in contrast to rSBP, which only binds the androgen. Therefore, we conclude that (1) docking of the two subunits creates an asymmetric steroid-binding site located at the interface between the subunits, and (2) only one face of the dimer defines the specificity for binding E2 by encompassing portion of a structural motif that recognizes the flat ring A of E2. The remaining portion, which recognizes the saturated ring A of DHT, is shared by both faces of the dimer. Because native monomers do not exist alone, the often-asked question of whether the SBP monomer binds steroid can be considered meaningless; steroid-binding activity is expressed only in the dimeric state. Finally, formation of the hybrid indicates that SBP dimerization represents a conserved event during the molecular evolution of SBP, suggesting that the structural elements responsible for dimerization will be homologous in SBPs from other species.

Animals↗
PubMed1996

Optimized standby rate reduces the ventricular rate variability in pacemaker patients with atrial fibrillation.

Patients with chronic atrial fibrillation (AF) and symptomatic bradycardia often receive ventricular-based pacemakers. However, many of these patients continue to have symptoms of palpitations, which may be due to ventricular rate variability. It has previously been shown that continuous ventricular pacing during AF has a stabilizing effect on the ventricular rate. Hence, a study was initiated to determine whether a patient-specific optimal ventricular standby rate that reduces the ventricular rate variability, without over-pacing, could be predicted. A ventricular rate stabilization (VRS) pacing algorithm that increases the pacing rate until instability is reduced below a threshold was developed. The VRS algorithm was utilized to determine a patient-specific standby rate in 15 patients with chronic AF, intact AV nodal conduction, and implanted pacemakers. The computer algorithm controlled a pacemaker programmer to automatically change the pacemaker's ventricular pacing rate via telemetry. Patients were studied for 15 minutes with VRS and for 15 minutes with 50 ppm fixed rate pacing (control). The results were as follows: (1) VRS versus control = P < 0.05; (2) mean ventricular pacing rate (ppm): 77 +/- 13 versus 50 +/- 0; (3) mean ventricular rate (beats/min): 82 +/- 13 versus 79 +/- 12; (4) ventricular rate coefficient of variation (%): 11 +/- 1 versus 22 +/- 5; (5) percent pacing: 75 +/- 8 versus 6 +/- 8; (6) percent of RR intervals less than minimum pacing interval eliminated: 58 +/- 12; (8) regression analysis: mean VRS pacing rate (beats/min) = 0.96 x mean control ventricular rate + 2.3, r2 = 0.85. We concluded that: (1) a moderate increase in the ventricular pacing rate was required to substantially stabilize the ventricular rate; (2) the resulting mean ventricular rate increased marginally; (3) a majority of RR cycles less than each patient's minimum pacing interval were eliminated; and (4) there was a linear relationship between the mean ventricular rate during control and the optimal ventricular pacing rate. Thus, a ventricular pacing rate close to the mean ventricular rate during control consistently reduced the ventricular variability. Although pacing at an increased ventricular standby rate reduces variability at rest, the optimal solution would likely be an adaptive rate algorithm that changes the ventricular standby rate as the mean intrinsic rate varies.

Aged↗
PubMed1995

A multicentre assessment of the specificity of ten anti-HBc screening tests.

Samples from 1828 donations were screened for anti-HBc at seven sites in the UK using kits supplied by 10 manufacturers. Only 10 (0.55%) donations were considered to have true anti-HBc reactivity and these were detected by all 10 kits. Additional markers of HBV infection were found in nine of these 10 donations. Additional reactives were found by all kits, the number ranging from 1 to 43. In the four more specific kits, the 10 true reactives were clearly distinguished from the 'false reactives' by the strength of the reaction. It is concluded that the reliance on a single ELISA test for anti-HBc diagnosis is unwise. The use of a second test known to be more specific than the screening ELISA is recommended.

Blood Donors↗
PubMed1994

Torsades de pointes ventricular tachycardia following right pneumonectomy: insights into the relation between right cardiac sympathetic nerve damage, QT intervals, and arrhythmias.

Polymorphic ventricular tachycardia in association with prolongation of the QT interval on the surface electrocardiogram (ECG) has long been recognized as an important cause of life threatening arrhythmias that can occur with congenital or acquired abnormalities of cardiac repolarization. One hypothesis of the origin of these arrhythmias states that overactivity of the left-sided sympathetic or under activity of the right-sided sympathetic neural input to the heart leads to prolonged repolarization and ventricular arrhythmias. This hypothesis has led to the application of left cervicothoracic sympathetectomy for control of arrhythmias in congenital long QT syndromes. Although animal models have shown QT prolongation following right stellate ganglionic section or left stellate stimulation, spontaneous ventricular arrhythmias following stellate stimulation or block in man have not been demonstrated. We report the case of a patient with life threatening ventricular arrhythmias following surgical damage to the right cardiothoracic sympathetic nerves.

Electrocardiography↗
PubMed1994

Abdominal aortic aneurysm and associated colorectal carcinoma: a management problem.

The increasing age of the population has led to the more common occurrence of multi-organ disease. Colorectal cancer (CRC) and abdominal aortic aneurysm (AAA) in the same patient is a difficult management problem. Over 10 years, 23 patients with CRC and AAA were treated at Concord Hospital. The management and outcome of these patients was reviewed to identify an optimum plan for patients with both conditions. The average age of patients was 71 years, ranging from 52 to 90 years. There was only one female patient in the series. In 19 of the patients, the AAA and CRC were synchronous, while in the other four patients the AAA and CRC were remote events. Within the group of patients with synchronous AAA and CRC. 12 had the diagnosis of both conditions made pre-operatively. However, in seven cases an unexpected AAA or CRC was found at operation for the other condition. Sixteen patients underwent resection of the CRC, while only eight underwent repair of the AAA. There were three deaths following CRC resection, two following AAA resection, and one following simultaneous CRC resection and AAA repair. Two of 10 patients with large (> 6 cm) AAA, who underwent CRC resection, ruptured the AAA in the postoperative period. A further patient ruptured 10 months following CRC resection. Colorectal cancer was given priority over AAA when these conditions were found simultaneously. The present study suggests that a large AAA (> 6 cm) should be either given preferential treatment, or resected simultaneously, in view of the high risk of rupture.

Aged↗
PubMed1993

Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS.

BACKGROUND: Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS: We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS: Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS: For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

AIDS-Related Opportunistic Infections↗
PubMed1993

The effect of prophylactic nitroglycerin infusion on the incidence of regional wall-motion abnormalities and ST segment changes in patients undergoing coronary artery bypass surgery.

The effects of nitroglycerin (NTG) on regional wall-motion abnormalities, ST segment changes, and the incidence of myocardial infarction (MI), cardiac failure, and mortality were studied in 30 patients undergoing coronary artery bypass. Patients received continuous infusions of either normal saline or NTG (1 microgram/kg per min [low dose] or 2 micrograms/kg per min [high dose]) beginning at anesthesia and continuing for 4 hours postoperatively. The occurrence of wall-motion abnormalities as detected by transesophageal echocardiography was 38 events in the normal saline group (N = 10). Significantly fewer events (p < 0.05) were recorded in the low dose and high dose NTG groups (20 events and 15 events, respectively) compared to controls. There were no significant differences between the control and NTG groups with regard to the incidence of Holter ST segment events or the incidence of MI, cardiac failure, or cardiac death. NTG reduced the incidence of echocardiographic wall-motion abnormalities in a dose dependent manner while having no significant effect on other parameters examined.

Coronary Artery Bypass↗
PubMed1991

A preliminary evaluation of 566C80 for the treatment of Pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome.

BACKGROUND: The drug 566C80 is an investigational hydroxynaphthoquinone that is active against Pneumocystis carinii in vitro and in animal models. Initial studies in humans indicate that 566C80 is safe and has adequate bioavailability after oral administration. METHODS: We conducted an open-label trial of 566C80 in 34 adults with the acquired immunodeficiency syndrome (AIDS) and untreated pneumocystis pneumonia. All the patients had a partial pressure of arterial oxygen of at least 60 mm Hg while breathing room air. They were enrolled sequentially in three cohorts taking 566C80 at different dosages, all administered orally: 750 mg three times daily for 5 days, then twice daily for 16 days; 750 mg three times daily for 21 days; and 750 mg four times daily for 21 days. RESULTS: All 34 patients survived, and 27 (79 percent) were successfully treated with 566C80 alone. The mean partial pressure of oxygen in 33 patients was 78 mm Hg at entry and 93 mm Hg after the course of 566C80 (P less than 0.001). In five patients (15 percent) the drug was discontinued because of lack of response. In four patients (12 percent), the drug was discontinued because of toxicity (fever and rash in two patients each). In two of these, treatment was considered to have succeeded because 566C80 was not discontinued because of toxicity until after day 14. Five of the successfully treated patients had rashes that resolved despite continued therapy. In nine patients, serum alanine aminotransferase levels rose above 100 U per liter. During the first three months after the completion of therapy, pneumocystis pneumonia recurred in 4 of the 27 successfully treated patients, and another 3 patients had recurrences between month 3 and month 6 of follow-up. The mean (+/- SEM) steady-state plasma levels of 566C80 were similar in the three cohorts: 16.3 +/- 2.10, 20.4 +/- 2.48, and 18.9 +/- 3.08 micrograms per milliliter in the patients taking the drug twice daily, three times daily, and four times daily, respectively. CONCLUSIONS: From these preliminary data, the investigational compound 566C80 appears to be a safe, effective, and well-tolerated therapy for P. carinii pneumonia of mild-to-moderate severity in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Primary structure of a novel barley gene differentially expressed in immature aleurone layers.

As a direct approach to elucidate the molecular biology of barley aleurone cell development, we differentially screened an aleurone cDNA library made from poly(A)+ RNA of immature grains for clones representing transcripts present in the aleurone but not in the starchy endosperm. For one of these clones, B22E, which hybridies to a 0.7 kb transcript, Northern and in situ hybridization revealed that expression is under complex spatial, temporal and hormonal control in barley grains. cDNAs corresponding to B22E transcripts were isolated from aleurone/pericarp and embryo of developing grains, and from germinating scutella. Among these were the nearly full-length aleurone/pericarp clone pB22E.a16 (541 bp). cDNAs matching the sequence of this clone (type 1 transcript) were found for all tissues investigated. In addition, cDNAs with an extra 12 bp insertion (type 2 transcript) were obtained from germinating scutella. The two different transcripts can encode novel barley proteins of 115 and 119 amino acids, respectively. A gene designated B22EL8 was isolated and sequenced; it encodes the type 1 B22E transcript and contains two introns of 145 and 125 bp. Particle bombardment of barley aleurone with a B22EL8 promoter-GUS (beta-glucuronidase) construct demonstrates that the promoter (3 kb) is active in developing barley grains. The promoter is not, however, active in the seeds of tobacco plants transgenic for the B22EL8 gene, indicating the existence of sequences specific for monocots. A comparison of 1.4 kb of upstream sequence of B22E with the maize c1 promoter reveals a number of short, identical sequences which may be responsible for aleurone cell-specific gene transcription.

Amino Acid Sequence↗
PubMed1991

An investigation of the safety of the blood reinfusion step used with tunneled venous access devices in children with cancer.

Infection has been identified as the most serious potential complication of the indwelling catheter. As a result, the primary nursing goal using the catheters is to prevent infection. Nurses must frequently manipulate the catheters when securing blood specimens and are concerned that this manipulation may serve as a source of infection for the immunocompromised pediatric oncology patient. One particular step in catheter manipulation during blood sampling is blood reinfusion, ie, residual blood in the catheter is withdrawn and set aside while a second sample is collected for laboratory analysis but is subsequently returned to the patient through the catheter. The purpose of this study was to examine this nursing procedure for its potential of contaminating the blood sample that was to be reinfused, or for the potential of reinfusing a sample that contained preexisting pathogens independent of the procedure itself. An experimental design was used with 21 patients randomly assigned to an experimental group (unclean procedure to exaggerate the potential to incur pathogens during the process), and 21 randomly assigned to a control group (usual clean procedure followed with the reinfusion sample). The usual blood sampling procedure was altered for all participants as the typical amount of blood that normally constitutes the reinsertion sample was not reinserted, but was instead used to complete certain microbial analyses. Of the 42 participants, 17 were male and 25 were female; 35 were white and seven were black; 22 were diagnosed with leukemias and 20 with solid tumors. The age range for participants was 2 to 20 years (mean = 9.4 years, SD = 4.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗