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Biomedical subjects

J Miles

Publications and source records attributed to J Miles.

At least 19 recordsLinked to original sources
PubMed2026

First UK use of bacteriophage therapy with DAIR for chronic Staphylococcus aureus prosthetic joint infection.

BACKGROUND: Chronic Staphylococcus aureus prosthetic joint infection (PJI) remains difficult to manage when surgical revision and long-term antibiotics are not feasible. Bacteriophage therapy is emerging as a potential adjunct, though experience in orthopedic infections, particularly in the United Kingdom, is limited. CASE SUMMARY: We report the first UK case of intra-articular bacteriophage therapy administered alongside debridement, antibiotics, and implant retention (DAIR) for chronic methicillin-sensitive Staphylococcus aureus knee PJI. An 81-year-old man with multiple comorbidities developed persistent infection following revision knee arthroplasty, with recurrent sinus formation despite multiple surgical washouts and prolonged suppressive antibiotics. Major revision surgery and amputation were not viable options. Following a multidisciplinary review through the UK Clinical Phage Network, targeted phage therapy was pursued as salvage treatment. Phage susceptibility testing identified an active lytic phage (ISP). The patient underwent open DAIR with intra-articular phage administration, adjunctive local antibiotics, short-course intravenous antimicrobials, and subsequent oral suppressive therapy. Two further intra-articular phage doses were administered postoperatively. Initial sinus closure occurred, but recurrence developed within 4 weeks. At 18 months, symptoms were partially improved with better mobility and reduced inflammation, though one sinus tract persisted. No significant adverse effects were observed. Whole-genome sequencing of pretreatment isolates demonstrated a predominantly ST5 S. aureus genotype with conserved biofilm-associated virulence genes and limited antimicrobial resistance in addition to clonal diversification consistent with chronic biofilm infection. CONCLUSION: This case demonstrates the feasibility and safety of intra-articular phage therapy during DAIR in a UK setting but highlights biological, logistical, and pharmacological factors that may limit efficacy in advanced chronic PJI.

Staphylococcus aureus↗
PubMed1996

Nurses' views of the decision not to resuscitate a patient.

The decision not to resuscitate a patient is a complex issue and there is little guidance for nurses on how such a decision is made. The aim of this study was, therefore, to explore the views and working practices of staff in relation to current guidelines and theories, using a situational analysis. Overall, the staff seemed to meet the criteria outlined in the guidelines, although there was little awareness of the guidelines. Nurses in the clinical area should be both educated in the recommendations for practice and should be consulted and involved in developing such recommendations.

Attitude of Health Personnel↗
PubMed1995

Atopic status in patients with brittle and non-brittle asthma: a case-control study.

BACKGROUND: Sensitization to inhaled and ingested allergens is an important process in determining the subsequent clinical expression of asthma. Allergen exposure has also been reported to be associated with admission to hospital with acute severe asthma. Patients with brittle asthma, characterized by widely variable peak expiratory flow are at increased risk of life-threatening episodes but the role of atopy in these patients is unknown. OBJECTIVE: To determine the atopic status of patients with brittle asthma using a case-control design. METHODS: We have assessed the atopic status by skin-prick tests to 19 common allergens, and total and specific immunoglobulin E (IgE) in 29 patients with well characterized brittle asthma and an age, sex and treatment-matched control group without brittle asthma. RESULTS: Mean weal diameters were higher in brittle compared to non-brittle asthma for grass pollen (4.64 vs 2.17; P = 0.01), horse hair (6.28 vs 2.64; P = 0.02), feathers (2.96 vs 1.52; P = 0.01), wheat (1.48 vs 0.66; P = 0.001) and chocolate (1.09 vs 0.41; P = 0.05). Mean radioallergosorbent (RAST) scores to house dust mite were also greater in brittle asthma patients (19.3 vs 7.65; P = 0.05). Patients with brittle asthma also exhibited a significantly greater degree of atopy when weal diameters to all 19 allergens were summated to produce an atopy score (brittle 44.35 vs non-brittle 23.72; P = 0.04). There were no significant differences between the two groups in either the number of positive skin tests (using a 4 mm definition of skin-test positivity), total IgE or RASTs (using a weak +ve score to define positivity). However, the use of differing definitions of atopy (1, 2, 3, 4 and 5 mm skin test weal diameters) resulted in marked intra-group variation in atopic status in both brittle and non-brittle asthma patients. CONCLUSIONS: The greater degree of atopy seen may be an important factor in patients with brittle asthma. The varying interpretations of the classification of what constitutes the presence or absence of atopy, based on mean weal diameters of skin-prick tests, or from IgE or RAST positivity shows that there is considerable potential variation in the degree of difference between the two groups depending on what criteria are used. Although internationally agreed definitions of atopic status have been devised a more rigorous application, or review of these guidelines needs to accompany future epidemiological studies of allergic sensitization.

Animals↗
PubMed1995

Effects of the normal nocturnal rise in cortisol on carbohydrate and fat metabolism in IDDM.

Plasma cortisol concentrations increase approximately three- to five-fold during sleep in healthy humans. To determine the effects of the normal nocturnal rise in cortisol on carbohydrate and fat metabolism independent of changes in endogenous insulin secretion, we studied the disposition of a mixed meal in individuals with insulin-dependent diabetes mellitus (IDDM) in whom the normal nocturnal rise in cortisol had been either prevented or mimicked by using metyrapone and a constant or variable hydrocortisone infusion. Insulin was infused intravenously on both occasions in amounts sufficient to create relative postprandial insulin deficiency. The nocturnal rise in cortisol resulted in an approximately 30 mg/dl greater (P < 0.001) peak postprandial glycemic excursion due to greater (P < 0.01) systemic glucose appearance and inappropriately low (P < 0.05) tissue glucose uptake. The latter was most evident when postprandial glucose concentrations in the presence and absence of the nocturnal rise in cortisol were matched by means of an exogenous glucose infusion to avoid the confounding effects of differences in glycemia. The nocturnal rise in cortisol also resulted in increased (P < 0.01) incorporation of 14CO2 into glucose (an index of gluconeogenesis), decreased (P < 0.05) carbohydrate oxidation, and increased (P < 0.05) rates of palmitate appearance, lipid oxidation, and beta-hydroxybutyrate concentrations. Thus the normal nocturnal rise in cortisol, independent of changes in insulin secretion, is an important regulator of postabsorptive and postprandial carbohydrate, fat, and ketone body metabolism in humans.

Adult↗
PubMed1994

Stereotactic radiosurgery for glioblastoma multiforme: report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage.

PURPOSE: Prospective evaluation of the toxicity and efficacy of radiosurgery with external beam radiotherapy in the management of newly diagnosed glioblastoma. METHODS AND MATERIALS: From 5/89 to 12/92, 31 out of 51 patients with glioblastoma multiforme underwent radiosurgery, in addition to 54 Gy in 1.8 Gy/fraction following biopsy (n = 12) or resection (n = 19). Eligibility required supratentorial glioblastoma, tumor not > 4 cm in > 1 axis, age > 18 years, and location > 1 cm from optic chiasm. Patient characteristics were: age 20-78 years (median = 57); 22 male, 9 female; Karnofsky score 20-90 (m = 70), and volume of 2.3-59.7 c.c. (m = 17.4). Eighteen patients were treated with 1 collimator, 5 with 2, 7 with 3, and 1 with 4; peripheral isodoses were 40-90% (m = 72.5) and minimum and maximum tumor dose ranges were 10-20 (m = 12) and 15-35 Gy (m = 18.75). Patients were followed clinically and radiographically every 8-12 weeks to analyze survival, quality of life, and toxicity. RESULTS: With a follow-up of 12-171 weeks, 8 out of 31 (26%) patients are alive. Median survival is 42 weeks. Twelve and 24-month actuarial survival are 38 and 28%. Comparison of the 2-year survival with previous Radiation Therapy Oncology Group patients was carried out using a nonparametric recursive partitioning technique and the observed vs. expected values are 28 vs. 9.7% (p < 0.05). Extent of resection and performance status were associated with improved survival in a multivariate analysis. No significant acute toxicity was encountered. Four patients (13%) developed clinically significant necrosis verified by biopsy or positron emission tomography scan at 9-59 weeks after radiosurgery. CONCLUSION: The improvement in median survival in broadly selected glioblastoma patients treated with radiosurgery is difficult to determine, but the 2-year survival may be superior. Future randomized trials of radiosurgery are recommended, and ad hoc use of this modality should be discouraged.

Adult↗
PubMed1994

Fibrodysplasia (myositis) ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary connective tissue disorder. Patients with FOP develop progressive ossification of muscle and connective tissue associated with pain and disability. Onset is typically in childhood, and congenital anomalies of the feet are an early sign of this condition. Pain and stiffness of the spine or an inflammatory mass are common presenting features of FOP. Involvement of the spine often leads to complete fusion mimicking ankylosing spondylitis. Studies of twins and families suggest that FOP is a genetically inherited autosomal dominant trait with complete penetrance but variable expressivity. While radionuclide imaging and computed tomography are very sensitive for new bone formation and greatly assist the diagnosis of FOP, unfortunately, effective therapy is unavailable. We present twins with FOP and review the clinical, radiographic, and genetic manifestations of this disorder.

Adult↗
PubMed1994

Learning disability subtypes and the effects of auditory and visual priming on visual event-related potentials to words.

Three learning-disability (LD) subtype groups and a normal control group of children were compared in their visual event-related potentials (ERPs) to primed and unprimed words. The LD subtypes were defined by deficient performance on tests of arithmetic (Group A), reading and spelling (Group RS), or both (Group RSA). The primed words were preceded by pictures or spoken words having a related meaning, while unprimed words were preceded by non-associated pictures or spoken words. For normal controls, N450 amplitude was greater to unprimed words than to words primed by pictures and spoken words. For Group A, N450 amplitude was reduced by spoken-word primes, but not by picture primes, an effect that demonstrates a deficit in processing visual-spatial information. For Group RS and Group RSA, neither picture nor spoken-word primes reduced N450 amplitude. These effects can be understood in terms of deficiencies in processing auditory-verbal information. Normal controls displayed a greater left- than right-hemispheric asymmetry in frontal N450 amplitude to unprimed words, an effect that is consistent with the association of skilled reading with hemispheric specialization. This asymmetry was absent in the ERPs of all the LD subtypes. The distinct ERP effects for the groups endorses the value of defining LD subtypes on the basis of patterns of deficits in arithmetic and reading and spelling.

Adolescent↗
PubMed1994

The determination of IgG subclass concentrations in serum by enzyme-linked immunosorbent assay: establishment of age-related reference ranges for cord blood samples, children aged 5-13 years and adults.

We describe a simple enzyme-linked immunosorbent assay for the measurement of immunoglobulin G (IgG) subclasses in serum. The microtitre plate is coated directly with diluted samples, standards or controls, blocked with phosphate-buffered saline containing 1% Tween to prevent non-specific protein binding to the plate, and each subclass assigned with specific mouse monoclonal antibody. The specific antibody is detected with alkaline-phosphatase linked anti-globulin and the colour development of the paranitrophenyl phosphate indicator reagent is measured at 405 nm until the highest concentration of standard gives an absorbance in excess of 1.4. Coefficients of variation measured at three concentration levels were less than 7% for within-assay variation and less than 10% for between-assay variation. Regression analysis of total IgG with the sum of the measured IgG subclasses gave a correlation coefficient of 0.932 (P < 0.001). The assay has been used to establish age-related reference ranges for serum IgG subclasses; these are found to be slightly different from those established for radioimmunodiffusion methods. Our study does not confirm the previously reported absence of IgG4 in normal individuals.

Adolescent↗
PubMed1993

Tracer disequilibrium in CO2 compartments during NaH14CO3 infusion.

The failure of labeled CO2 to equilibrate between extracellular and intracellular CO2 compartments may influence the accuracy of substrate oxidation measurements during infusion of carbon-labeled tracers because it may generate errors in estimate of fixation of labeled CO2 derived from control experiments in which labeled bicarbonate is infused. In this study, normal volunteers received a 14-hour overnight primed continuous infusion of NaH14CO3. Over the last 4 hours of the study, steady-state conditions were achieved in the specific activities (SAs) of expired 14CO2 and plasma urea, which was used as a probe for hepatic intracellular CO2 SA. Plasma urea SA was approximately 17% lower than expired CO2 SA (46.4 +/- 5.6 v 56.8 +/- 3.9 disintegrations per minute.mumol-1, P < .02). Fractional 14CO2 recovery was 94.8% +/- 0.8%; when corrected for failure to equilibrate with intracellular CO2, fractional recovery was 89.5% +/- 1.9%. These data indicate that compartmentalization of CO2 may occur in humans. The duration of our experiments, required because of the long half-life of plasma urea, may have minimized the apparent magnitude of compartmentalization. Furthermore, it is possible that compartmentalization in extrahepatic tissues could be of either lesser or greater magnitude than that which we observed in liver. Whether this phenomenon contributes to incomplete recovery of 14CO2 during NaH14CO3 infusion cannot be determined from our results. Additional studies using different experimental approaches will be required to better measure CO2 compartmentalization.

Adolescent↗
PubMed1993

Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans.

Glucocorticoid concentrations vary throughout the day. To determine whether an increase in cortisol similar to that present during sleep is of physiologic significance in humans, we studied the disposition of a mixed meal when the nocturnal rise in cortisol was mimicked or prevented using metyrapone plus either a variable or constant hydrocortisone infusion. When glucose concentrations were matched with a glucose infusion, hepatic glucose release (2.6 +/- 0.2 vs. 1.5 +/- 0.4 nmol/kg per 6 h) was higher (P < 0.05) while glucose disappearance (5.9 +/- 0.3 vs. 7.3 +/- 0.9 mmol/kg per 6 h) and forearm arteriovenous glucose difference (64 +/- 24 vs. 231 +/- 62 mmol/dl per 6 h) were lower (P < 0.05) during the variable than basal infusion. The greater hepatic response during the variable cortisol infusion was mediated (at least in part) by inhibition of insulin and stimulation of glucagon secretion as reflected by lower (P < 0.05) C-peptide (0.29 +/- 0.01 vs. 0.38 +/- 0.04 mmol/liter per 6 h) and higher (P < 0.05) glucagon (42.7 +/- 2.0 vs. 39.3 +/- 1.8 ng/ml per 6 h) concentrations. In contrast, the decreased rates of glucose uptake appeared to result from a state of "physiologic" insulin resistance. The variable cortisol infusion also increased (P < 0.05) postprandial palmitate appearance as well as palmitate, beta-hydroxybutyrate, and alanine concentrations, suggesting stimulation of lipolysis, ketogenesis, and proteolysis. We conclude that the circadian variation in cortisol concentration is of physiologic significance in normal humans.

Adult↗
PubMed1993

A radioimmunoassay for human urinary prealbumin.

We describe a validated radioimmunoassay for prealbumin in urine. Using timed overnight urine samples, the normal reference range was less than 10-148 micrograms/L; or less than 1.8-9.6 micrograms/mmol creatinine, excretion in women being significantly greater than in men (P < 0.05); or less than 7.3-114 ng/min with no significant difference in excretion rate between the sexes. Urines exhibited loss of immunoreactivity after storage at -20 degrees C and thawing. No such loss occurred after storage for 4 weeks at 4 degrees C or room temperature. The urinary excretion of prealbumin was highly correlated with that of albumin (r = 0.85), and clearance relative to creatinine was 2 x 10(-6), the same order as that of albumin.

Adolescent↗
PubMed1992

Protein affinity chromatography with purified yeast DNA polymerase alpha detects proteins that bind to DNA polymerase.

We have overexpressed the POL1 gene of the yeast Saccharomyces cerevisiae and purified the resulting DNA polymerase alpha polypeptide in an apparently intact form. We attached the purified DNA polymerase covalently to an agarose matrix and used this matrix to chromatograph extracts prepared from yeast cells. At least six proteins bound to the yeast DNA polymerase alpha matrix that did not bind to a control matrix. We speculate that these proteins might be DNA polymerase alpha accessory proteins. Consistent with this interpretation, one of the binding proteins, which we have named POB1 (polymerase one binding), is required for normal chromosome transmission. Mutations in this gene cause increased chromosome loss and an abnormal cell morphology, phenotypes that also occur in the presence of mutations in the yeast alpha or delta polymerase genes. These results suggest that the interactions detected by polymerase affinity chromatography are biologically relevant and may help to illuminate the architecture of the eukaryotic DNA replication machinery.

Chromatography, Affinity↗
PubMed1992

Evidence that POB1, a Saccharomyces cerevisiae protein that binds to DNA polymerase alpha, acts in DNA metabolism in vivo.

Potential DNA replication accessory factors from the yeast Saccharomyces cerevisiae have previously been identified by their ability to bind to DNA polymerase alpha protein affinity matrices (J. Miles and T. Formosa, Proc. Natl. Acad. Sci. USA 89:1276-1280, 1992). We have now used genetic methods to characterize the gene encoding one of these DNA polymerase alpha-binding proteins (POB1) to determine whether it plays a role in DNA replication in vivo. We find that yeast cells lacking POB1 are viable but display a constellation of phenotypes indicating defective DNA metabolism. Populations of cells lacking POB1 accumulate abnormally high numbers of enlarged large-budded cells with a single nucleus at the neck of the bud. The average DNA content in a population of cells lacking POB1 is shifted toward the G2 value. These two phenotypes indicate that while the bulk of DNA replication is completed without POB1, mitosis is delayed. Deleting POB1 also causes elevated levels of both chromosome loss and genetic recombination, enhances the temperature sensitivity of cells with mutant DNA polymerase alpha genes, causes increased sensitivity to UV radiation in cells lacking a functional RAD9 checkpoint gene, and causes an increased probability of death in cells carrying a mutation in the MEC1 checkpoint gene. The sequence of the POB1 gene indicates that it is identical to the CTF4 (CHL15) gene identified previously in screens for mutations that diminish the fidelity of chromosome transmission. These phenotypes are consistent with defective DNA metabolism in cells lacking POB1 and strongly suggest that this DNA polymerase alpha-binding protein plays a role in accurately duplicating the genome in vivo.

Amino Acid Sequence↗
PubMed1991

Measurement of plasma acetate kinetics using high-performance liquid chromatography.

Previous studies suggest that plasma acetate may be an important fuel in man, accounting for approximately 10% of energy expenditure. Available methods for the determination of plasma acetate kinetics are difficult and time consuming. We describe here a procedure for the determination of plasma acetate concentration and specific activity using automated high-performance liquid chromatography that is precise and sensitive and accommodates large numbers of samples. The procedure involves extraction from plasma with diethyl ether, derivatization with bromoacetophenone, and separation on a C-18 reversed-phase column. The specific activities of D-beta-hydroxybutyrate and lactate can also be determined. Acetate turnover was measured in four dogs and was similar to that previously reported in sheep and humans. Transport of [14C]acetate into red blood cells was negligible.

3-Hydroxybutyric Acid↗
PubMed1991

Give us a daily bed.

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Ambulatory Surgical Procedures↗