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Biomedical subjects

S Freeman

Publications and source records attributed to S Freeman.

At least 19 recordsLinked to original sources
PubMed2007

A prospective study of admissions for febrile neutropenia in secondary paediatric units in South East England.

BACKGROUND: The Paediatric Oncology Centres (POCs) treating childhood cancer in South East England produce unified supportive care guidelines for use in the secondary pediatric (shared care) units. This study evaluated the adherence to current guidelines for febrile neutropenia (FN) and documented outcome in terms of bacterial isolates, antibiotic resistance patterns, length of hospital stay, and mortality. PROCEDURE: Prospective study of pediatric FN admissions between July 2001 and December 2002. RESULTS: Data were received on 433 eligible FN episodes in 212 patients. The recommended empirical antibiotics (piptazobactam + gentamicin) were used in 354 (82%) admissions. Blood cultures were positive in 129 episodes (30%). Gram-positive organisms predominated (120/149 organisms isolated) and the majority were coagulase-negative Staphylococci (95/120). There were 27 Gram-negative isolates and 1 fungal isolate. No Gram-negative isolate was resistant to both first-line antibiotics. Only one death was recorded in the study group. The median length of hospital stay was 5 days. CONCLUSIONS: We obtained data on a large number of shared care episodes of FN. The antibiotic guidelines were followed in most episodes. Bacteremia was common, but little resistance to first-line antibiotics was documented among Gram-negative isolates, confirming the safety of the strategy in our population.

Adolescent↗
PubMed2006

Sensitivity of glycogen phosphorylase isoforms to indole site inhibitors is markedly dependent on the activation state of the enzyme.

BACKGROUND AND PURPOSE: Inhibition of hepatic glycogen phosphorylase is a potential treatment for glycaemic control in type 2 diabetes. Selective inhibition of the liver phosphorylase isoform could minimize adverse effects in other tissues. We investigated the potential selectivity of two indole site phosphorylase inhibitors, GPi688 and GPi819. EXPERIMENTAL APPROACH: The activity of glycogen phosphorylase was modulated using the allosteric effectors glucose or caffeine to promote the less active T state, and AMP to promote the more active R state. In vitro potency of indole site inhibitors against liver and muscle glycogen phosphorylase a was examined at different effector concentrations using purified recombinant enzymes. The potency of GPi819 was compared with its in vivo efficacy at raising glycogen concentrations in liver and muscle of Zucker (fa/fa) rats. KEY RESULTS: In vitro potency of indole site inhibitors depended upon the activity state of phosphorylase a. Both inhibitors showed selectivity for liver phosphorylase a when the isoform specific activities were equal. After 5 days dosing of GPi819 (37.5 micromol kg(-1)), where free compound levels in plasma and tissue were at steady state, glycogen elevation was 1.5-fold greater in soleus muscle than in liver (P < 0.05). CONCLUSIONS AND IMPLICATIONS: The in vivo selectivity of GPi819 did not match that seen in vitro when the specific activities of phosphorylase a isoforms are equal. This suggests T state promoters may be important physiological regulators in skeletal muscle. The greater efficacy of indole site inhibitors in skeletal muscle has implications for the overall safety profile of such drugs.

Animals↗
PubMed2006

Biological treatment of heavy metals in acid mine drainage using sulfate reducing bioreactors.

The uncontrolled release of acid mine drainage (AMD) from abandoned mines and tailing piles threatens water resources in many sites worldwide. AMD introduces elevated concentrations of sulfate ions and dissolved heavy metals as well as high acidity levels to groundwater and receiving surface water. Anaerobic biological processes relying on the activity of sulfate reducing bacteria are being considered for the treatment of AMD and other heavy metal containing effluents. Biogenic sulfides form insoluble complexes with heavy metals resulting in their precipitation. The objective of this study was to investigate the remediation of AMD in sulfate reducing bioreactors inoculated with anaerobic granular sludge and fed with an influent containing ethanol. Biological treatment of an acidic (pH 4.0) synthetic AMD containing high concentrations of heavy metals (100 mg Cu(2+)l(-1); 10 mg Ni(2+)l(-1), 10 mg Zn(2+)l(-1)) increased the effluent pH level to 7.0-7.2 and resulted in metal removal efficiencies exceeding 99.2%. The highest metal precipitation rates attained for Cu, Ni and Zn averaged 92.5, 14.6 and 15.8 mg metal l(-1) of reactor d(-1). The results of this work demonstrate that an ethanol-fed sulfidogenic reactor was highly effective to remove heavy metal contamination and neutralized the acidity of the synthetic wastewater.

Acids↗
PubMed2005

Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas.

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.

Adenoviridae↗
PubMed2005

A team approach to musculo-skeletal disorders.

INTRODUCTION: The majority of patients with musculo-skeletal problems referred to hospitals in the UK have to wait for months, if not over a year, before finally seeing an orthopaedic surgeon. In Stobhill Hospital, Glasgow, the waiting time for an out-patient appointment was 182 days in 1995, with only 20% of the referrals requiring surgery. The aim of this paper was to reduce the out-patient waiting times based on a co-ordinated team approach. METHODS: An outpatient musculo-skeletal service was developed over a 7-year period at Stobhill Hospital. The traditional consultant-based model, in which the consultant and a trainee saw all new patients referred to the hospital, was gradually replaced with a team approach, based on continuous reconfiguration of the roles of the orthopaedic surgeon and rheumatologist and extending the roles of nurses, physiotherapists and podiatrists. This was achieved by: (i) protocol-based daily triage for all referrals to the most appropriate health professional in the team, by the senior out-patient nursing staff; (ii) allocation of appointments based on clinical priority, with a fast-track for urgent cases; and (iii) improvement of inter-disciplinary communication, facilitating the retraction as well as the extension of traditional roles. RESULTS: Despite the number of GP referrals to the orthopaedic out-patient department at Stobhill nearly doubling in a period of 5 years, the out-patient waiting time decreased by about 50% (90 days from 182 days). This reduction in waiting times improved patient and GP satisfaction levels. We also noticed an improved morale and personal development of the health professionals as they saw patients appropriate to their skills and expertise. CONCLUSION: The team's experience demonstrates the effectiveness of a team approach in tackling what is often seen as the insoluble problem of orthopaedic waiting times. This is based on excellent communication and collaboration, with a clear aim of improving patient care that is evidence based.

Clinical Protocols↗
PubMed2005

Comparison of chemo-, hetero- and mixotrophic denitrification in laboratory-scale UASBs.

This study investigated removal of sulfide and p-cresol linked to denitrification in laboratory-scale upflow anaerobic granular sludge bed (UASB) bioreactors. Three parallel denitrification bioreactors were run for nine months, which were operated under chemolithoautotrophic conditions (i.e., using sulfide as electron donor -e-donor- and bicarbonate as C source); heterotrophic conditions (with p-cresol as e-donor and C source), and mixotrophic conditions (utilizing both sulfide and p-cresol as electron donors), respectively. The average hydraulic retention time and nitrate load applied to the bioreactors was 13.4 h and 1,240 mg N-NO3/l/day, respectively. The nitrate removal efficiency was 89, 95 and 99%, respectively, for the chemo-, hetero- and mixotrophic reactors. The mixotrophic UASB removed both sulfide and p-cresol almost completely, indicating that simultaneous removal of the inorganic and organic e-donors occurred. Nitrite was seldom observed as an intermediate. N2O gas and methane concentrations in the biogas were also negligible. These results indicate that mixotrophic denitrification with phenols and sulfide is feasible in high rate UASB reactors.

Bacteria, Anaerobic↗
PubMed2003

Identification of a novel class of inhibitor of human and Escherichia coli thymidine phosphorylase by in silico screening.

Structure-based computational screening of the National Cancer Institute database of anticancer compounds identified novel non-nucleobase-derived inhibitors of human thymidine phosphorylase as candidates for lead optimization. The hierarchical in silico screening strategy predicted potentially strong low molecular weight ligands exhibiting a range of molecular scaffolds. Of the thirteen ligands assayed for activity, all displayed inhibitory activity against Escherichia coli thymidine phosphorylase. One compound, hydrazine carboxamide 2-[(1-methyl-2,5-dioxo-4-pentyl-4-imidazolidinyl)methylene], was found to inhibit E. coli thymidine phosphorylase with an IC(50) value of 20 microM and an IC(50) value of 77 microM against human thymidine phosphorylase. As this hydantoin derivative lacks the undesirable ionic sites of existing tight-binding nucleobase-derived inhibitors, such as 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]uracil hydrochloride, it provides an opportunity for the design of potent thymidine phosphorylase inhibitors with improved pharmacokinetic properties.

Binding Sites↗
PubMed2003

Oral lichenoid lesions (OLL) and mercury in amalgam fillings.

84 patients with oral lichenoid lesions (OLL) were seen in the contact dermatitis clinic. All these patients had reticulate, lacy, plaque-like or erosive lichenoid changes adjacent to amalgam fillings. Patch testing to metallic mercury, 0.1% thimerosal, 1% ammoniated mercury, 0.1% mercuric chloride, and in some cases 0.05% phenylmercuric nitrate and amalgam discs was undertaken. 33 (39%) patients had positive patch test findings. 30/33 patch test positive patients had replacement of their amalgam fillings, with 28 (87%) patients experiencing improvement of symptoms and signs within 3 months. This confirms that mercury allergy is a factor in the pathogenesis of OLL in some cases. In cases where patch test negative patients improve with amalgam replacement, mercury may be acting as an irritant in the pathogenesis of OLL.

Adult↗
PubMed2003

Fungal biology and agriculture: revisiting the field.

Plant pathology has made significant progress over the years, a process that involved overcoming a variety of conceptual and technological hurdles. Descriptive mycology and the advent of chemical plant-disease management have been followed by biochemical and physiological studies of fungi and their hosts. The later establishment of biochemical genetics along with the introduction of DNA-mediated transformation have set the stage for dissection of gene function and advances in our understanding of fungal cell biology and plant-fungus interactions. Currently, with the advent of high-throughput technologies, we have the capacity to acquire vast data sets that have direct relevance to the numerous subdisciplines within fungal biology and pathology. These data provide unique opportunities for basic research and for engineering solutions to important agricultural problems. However, we also are faced with the challenge of data organization and mining to analyze the relationships between fungal and plant genomes and to elucidate the physiological function of pertinent DNA sequences. We present our perspective of fungal biology and agriculture, including administrative and political challenges to plant protection research.

Agriculture↗
PubMed2001

TNF-alpha controls intracellular mycobacterial growth by both inducible nitric oxide synthase-dependent and inducible nitric oxide synthase-independent pathways.

The role of TNF-alpha in the control of mycobacterial growth in murine macrophages was studied in vitro. Infection of macrophages from TNF-alpha gene disrupted (TNF-knockout (KO)) mice with recombinant Mycobacterium bovis bacillus Calmette Guérin (BCG) expressing the vector only (BCG-vector) resulted in logarithmic growth of the intracellular bacilli. Infection with BCG-secreting murine TNF-alpha (BCG-TNF) led to bacillary killing. Killing of BCG-TNF was associated with rapid accumulation of inducible NO synthase (iNOS) protein and the production of nitrite. The uncontrolled growth of BCG-vector was associated with low iNOS expression but no nitrite production. Thus, iNOS expression appears to be TNF-alpha independent but iNOS generation of NO requires TNF-alpha. In cultures of TNF-KO macrophages infected with BCG-TNF, inhibition of iNOS by aminoguanidine (AMG) abolished the killing of the bacilli. However, the growth of the organisms was still inhibited, suggesting an iNOS-independent TNF-alpha-mediated growth inhibition. To confirm this, macrophages from iNOS-KO mice were infected with either BCG-vector or BCG-TNF. As expected, no nitrite was detected in the culture medium. TNF-alpha was detected only when the cells were infected with BCG-TNF. In the iNOS-KO macrophages, the growth of BCG was inhibited only in the BCG-TNF infection. These results suggest that in the absence of iNOS activity, TNF-alpha stimulates macrophages to control the growth of intracellular BCG. Thus, there appears to be both a TNF-alpha-dependent-iNOS-dependent killing pathway as well as a TNF-alpha-dependent-iNOS-independent growth inhibitory pathway for the control of intracellular mycobacteria in murine macrophages.

Animals↗
PubMed2001

Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha /beta.

To understand how virulent mycobacteria subvert host immunity and establish disease, we examined the differential response of mice to infection with various human outbreak Mycobacterium tuberculosis clinical isolates. One clinical isolate, HN878, was found to be hypervirulent, as demonstrated by unusually early death of infected immune-competent mice, compared with infection with other clinical isolates. The differential effect on survival required lymphocyte function because severe combined immunodeficiency (SCID) mice infected with HN878 or other clinical isolates all died at the same rate. The hypervirulence of HN878 was associated with failure to induce M. tuberculosis-specific proliferation and IFN-gamma production by spleen and lymph node cells from infected mice. In addition, 2- to 4-fold lower levels of tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-12, and IFN-gamma mRNAs were observed in lungs of HN878-infected mice. IL-10, IL-4, and IL-5 mRNA levels were not significantly elevated in lungs of HN878 infected mice. In contrast, IFN-alpha mRNA levels were significantly higher in lungs of these mice. To further investigate the role of Type 1 IFNs, mice infected with HN878 were treated intranasally with purified IFN-alpha/beta. The treatment resulted in increased lung bacillary loads and even further reduced survival. These results suggest that the hypervirulence of HN878 may be due to failure of this strain to stimulate Th1 type immunity. In addition, the lack of development of Th1 immunity in response to HN878 appears to be associated with increased induction of Type 1 IFNs.

Animals↗
PubMed2001

Surgical treatment of atrial fibrillation using radiofrequency energy.

BACKGROUND: The Maze III procedure for atrial fibrillation (AF) is effective but has not been used widely due to its complexity, bleeding risk, and added operative time. Surgical radiofrequency ablation may simplify the procedure and make intraoperative correction of AF more accessible and widely performed. METHODS: Endocardial pulmonary venous isolation was performed on 48 patients with AF undergoing concurrent operation using temperature-controlled radiofrequency energy delivered through a hand-held flexible probe. Additional right-sided lesions were made at the surgeon's discretion. RESULTS: Forty-two patients were appropriate for analysis (6 died). These patients had an AF duration of 4.8 +/- 6.4 years. At a mean follow-up of 138 +/- 96 days, 34 patients were in sinus rhythm. We were unable to demonstrate a difference in outcome based on AF duration, left atrial size, or addition of right-sided lesions. CONCLUSIONS: Radiofrequency atrial ablation was effective in 81% of patients with AF at restoring sinus rhythm at an average follow-up of 4 months. This procedure is simple to perform and should broaden the number of patients that receive an AF treatment procedure during concurrent cardiac operation.

Adult↗
PubMed2001

The latency of auditory nerve brainstem evoked responses to air- and bone-conducted stimuli.

The auditory nerve brainstem evoked responses (ABRs) to bone conduction (BC) stimuli are longer in latency than those to air conduction (AC). In order to study the mechanism of this difference, ABR wave I was recorded in experimental animals in response to low intensity (0-20 dB above their threshold) logon stimuli delivered by BC and by using the same bone vibrator to generate the air-conducted stimulus. The BC stimuli were delivered to skull bone, and directly to the contents of the cranial cavity (brain and cerebrospinal fluid) through a craniotomy. ABR wave I in response to BC stimuli delivered to skull bone was significantly longer in latency than that to BC delivered on the brain, while there was no latency difference between AC stimuli and BC to the brain. Furthermore, the vibration (measured with an accelerometer) recorded on the brain during BC stimulation of skull bone was always delayed compared to that measured on the skull. Thus there is a delay in the transfer of vibratory energy from the skull bone to the underlying contents of the cranial cavity. From there, the delayed vibrations of the contents of the cranial cavity are transmitted to the inner ear. This is probably the mechanism of the longer latency BC response compared to the AC response.

Acoustic Stimulation↗
PubMed2001

A comparative study of the asparagine-linked oligosaccharides on siglec-5, siglec-7 and siglec-8, expressed in a CHO cell line, and their contribution to ligand recognition.

The siglecs (sialic acid-binding immunoglobulin-like lectins) mediate sialic acid-dependent cellular interactions and may in some cases signal through SH2-binding domains. In addition to the previously characterized siglecs, sialoadhesin, CD22, CD33 and myelin-associated glycoprotein, several new ones, siglec-5, siglec-7 and siglec-8, have recently been cloned. Although these novel receptors have generated considerable interest as therapeutic targets because of their expression pattern on immune cells, very little is known about how their lectin activity is regulated. Previous studies with sialoadhesin, CD22 and CD33 have shown that siglec glycosylation has significant effects on binding. To determine any differences in the glycan composition of siglec-5, siglec-7 and siglec-8 that may modify their function, we released and characterized the N-linked oligosaccharide distribution in these three glycoproteins. The glycan pools from siglec-5 and siglec-7 contained a larger proportion of sialylated and core-fucosylated biantennary, triantennary and tetra-antennary oligosaccharides, whereas the carbohydrate mixture released from siglec-8 is noticeably less sialylated and is more abundant in 'high-mannose'-type glycans. In addition, we show that, in contrast with CD22 and CD33, mutating the conserved potentially N-linked glycosylation site in the first domain has no effect on binding mediated by siglec-5 or siglec-7.

Amino Acid Motifs↗
PubMed2001

Cheilitis caused by contact urticaria to mint flavoured toothpaste.

A 26-year-old woman presented with a 12-month history of persistent dermatitis of the lips. She had failed to respond to cosmetic avoidance and therapeutic measures. Patch testing was negative, including her toothpaste and toothpaste flavours. She defied diagnosis until an acute flare followed immediately after dental treatment with a mint flavoured tooth cleaning powder. This led us to prick test her to mint leaves and this was positive. Her cheilitis settled after changing from her mint-flavoured toothpaste. A diagnosis of contact urticaria should be considered in cases of cheilitis of unknown cause.

Adult↗
PubMed2001

Allergic contact stomatitis caused by acrylic monomer in a denture.

A 71-year-old edentulous man developed a severely painful red mouth at sites of contact with a new denture. Patch testing showed allergy to samples of the denture material and to 2-hydroxyethyl methacrylate. Patch testing to methyl methacrylate was negative. Prolonged boiling of the denture resulted in reversal of his symptoms and samples of this fully cured denture material produced negative patch tests. While allergy to acrylates is a rare cause of stomatitis, this possibility must be considered in patients presenting with oral symptoms. Material safety data sheets are unreliable in providing information regarding the type of acrylate present in the material. Hence, patch testing should be performed with a battery of acrylate allergens as well as with small samples of the denture material.

Acrylic Resins↗