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Biomedical subjects

C J Thompson

Publications and source records attributed to C J Thompson.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of ibuprofen-loaded microspheres prepared from novel copolyesters.

The utility of two novel linear random copolyesters to encapsulate and control the release of ibuprofen, via microspheres, was investigated. Various manufacturing parameters, including temperature, disperse phase volume and polymer:ibuprofen ratios were altered during the microsphere production. The effects of these changes on the morphological characteristics of the microspheres, yield, drug loading, encapsulation efficiency and drug release rates were examined. The diameter of the microspheres ranged from 36 to 89 microm and showed both smooth and ridged surfaces. Microsphere diameter was probably determined by the internal phase volume, while surface morphology was controlled by manufacturing temperature. Greater encapsulation efficiency was obtained by increasing the polymer:ibuprofen ratio and by reducing the internal phase volume. For all batches there was an initial burst drug release into phosphate buffer (pH 7.4) over the first 2-4h, which was followed by a much slower release rate over the remaining time period. Drug release rates during both these phases were dependent upon the amount and nature of the polymer in the microspheres, noting that the more hydrophilic polymer provided faster release rates. Ibuprofen solubility appeared to play a dominant role in controlling release, although both encapsulation efficiency and microsphere morphology were also contributing factors.

Analgesics, Non-Narcotic↗
PubMed2006

Adipsic diabetes insipidus following pituitary surgery for a macroprolactinoma.

Adipsic diabetes insipidus (ADI) is a rare condition in which thirst, an essential clinical feature for the prevention of hypernatraemic dehydration, is absent. We report the first case of adipsic diabetes insipidus to occur following surgery for a pituitary macroprolactinoma, with loss of both osmoregulated and baroregulated vasopressin release. Following extensive surgery for a vision threatening macroprolactinoma a 14-year-old boy developed profound hypernatraemia with absent thirst sensation. Detailed investigation, with hypertonic saline infusion and trimetaphan infusion, revealed absence of both osmoregulatory and baroregulatory release of vasopressin. We discuss the investigation and management of such patients and the physiology of hypothalamic-neurohypophyseal dysfunction in such patients.

Adolescent↗
PubMed2004

Downward resetting of the osmotic threshold for thirst in patients with SIADH.

The syndrome of inappropriate antidiuretic hormone (SIADH) is characterized by euvolemic hyponatremia. Patients with SIADH continue to drink normal amounts of fluid, despite plasma osmolalities well below the physiological osmotic threshold for onset of thirst. The regulation of thirst has not been previously studied in SIADH. We studied the characteristics of osmotically stimulated thirst and arginine vasopressin (AVP) secretion in eight subjects with SIADH and eight healthy controls and the nonosmotic suppression of thirst and AVP during drinking in the same subjects. Subjects underwent a 2-h infusion of hypertonic (855 mmol/l) NaCl solution, followed by 30 min of free access to water. Thirst rose significantly in both SIADH (1.5 +/- 0.6 to 8.0 +/- 1.2 cm, P < 0.0001) and controls (1.8 +/- 0.8 to 8.4 +/- 1.5 cm, P < 0.0001), but the osmotic threshold for thirst was lower in SIADH (264 +/- 5.5 vs. 285.9 +/- 2.8 mosmol/kgH(2)O, P < 0.0001). SIADH subjects drank volumes of water similar to controls after cessation of the infusion (948.8 +/- 207.6 vs. 1,091 +/- 184 ml, P = 0.23). The act of drinking suppressed thirst in both SIADH and controls but did not suppress plasma AVP concentrations in SIADH compared with controls (P = 0.007). We conclude that there is downward resetting of the osmotic threshold for thirst in SIADH but that thirst responds to osmotic stimulation and is suppressed by drinking around the lowered set point. In addition, we demonstrated that drinking does not completely suppress plasma AVP in SIADH.

Adult↗
PubMed2004

Abnormal regulation of thirst and vasopressin secretion following surgery for craniopharyngioma.

OBJECTIVE: In this study we aimed to establish the frequency of postoperative diabetes insipidus and the incidence and characteristics of abnormalities of thirst in a cohort of patients with craniopharyngioma, in whom neurosurgery had been performed. DESIGN: Diabetes insipidus was determined by either standard criteria for diagnosis in the immediate postoperative period, or by water deprivation test, in all craniopharyngioma and pituitary tumour patients who underwent surgery in Beaumont Hospital between the years 1986 and 1998. Osmoregulated thirst and vasopressin release were studied during a 2-h infusion of hypertonic (5%) saline followed by a 30-min period of free access to water. PATIENTS: Data on the incidence of postoperative diabetes insipidus was collected in 26 patients with craniopharyngioma and 154 patients with pituitary adenomata. We recruited 16 healthy control patients, 16 patients with cranial diabetes insipidus following pituitary tumour surgery and 16 patients with cranial diabetes insipidus following craniopharyngioma resection for the hypertonic saline infusion study. RESULTS: Twenty-five patients out of 26 (96%) patients developed diabetes insipidus after surgery for craniopharyngioma, a much higher incidence than after surgery for suprasellar (26/88, 30%, P < 0.001) or intrasellar pituitary tumours (9/66, 14%, P < 0.001). Hypertonic saline infusion identified abnormal thirst responses in five of the 16 craniopharygioma patients studied; all of the pituitary tumour patients had a normal thirst response. Three of the craniopharyngioma patients had adipsic diabetes insipidus whilst two had polydipsic diabetes insipidus. CONCLUSION: This study demonstrates following surgery for craniopharyngioma there is a high incidence of cranial diabetes insipidus and a significant incidence of abnormal thirst responses to osmotic stimuli.

Adult↗
PubMed2003

Improved patient survival in recipients of simultaneous pancreas-kidney transplant compared with kidney transplant alone in patients with type 1 diabetes mellitus and end-stage renal disease.

BACKGROUND: There are emerging data that simultaneous pancreas-kidney transplant (SPK) prolongs life compared with kidney transplant alone (KTA) in type 1 diabetics with end-stage renal disease. This study was a retrospective comparison of SPK with KTA in patients with type 1 diabetes. METHODS: Between 1 January 1992 and 30 April 2002, 101 patients with type 1 diabetes were transplanted. Fifty-one of these patients received a KTA and 50 had a SPK. All patients underwent coronary angiography with surgical correction of any coronary artery disease before being listed. All patients who underwent SPK received quadruple immunosuppressive therapy consisting of antilymphocyte globulin, calcineurin inhibitor (tacrolimus or cyclosporin), azathioprine and steroids. Those who underwent KTA received calcineurin inhibitor (tacrolimus or cyclosporin), azathioprine and steroids. RESULTS: Patient survival at 1, 3, 5 and 8 years was 96, 93, 89 and 77 per cent respectively after SPK, and 93, 75, 57 and 47 per cent respectively after KTA (P = 0.018 at 8 years). CONCLUSION: The addition of pancreatic transplantation prolongs life in type 1 diabetic patients with renal failure compared with renal transplantation alone.

Adult↗
PubMed2003

The albuminuric action of atrial natriuretic peptide is not modified by ACE-inhibition with perindopril in Type 2 diabetes.

AIMS: Atrial natriuretic peptide (ANP) increases urine albumin excretion (UAER) in humans with Type 1 diabetes. The aim of this study was to establish if ANP increases UAER in microalbuminuric subjects with Type 2 diabetes and to examine whether the albuminuric action of ANP was inhibited by pre-treatment with the ACE-inhibitor perindopril. METHODS: Seven microalbuminuric, normotensive males with Type 2 diabetes were entered into a randomised, double-blind, three-armed study of (i) intravenous infusion of ANP (0.25 microg/kg/min in 0.9% NaCl) after 3 weeks' pre-treatment with placebo, (ii) intravenous infusion of vehicle (0.9% NaCl only) after 3 weeks' pre-treatment with placebo, or (3) intravenous infusion of ANP (0.25 microg/kg/min in 0.9% NaCl) after 3 weeks' pre-treatment with perindopril, 4 mg daily. RESULTS: Baseline parameters were similar on all three study days. During the placebo/vehicle arm there was no change in urine flow rate (UFR, P=0.61), urine cyclic guanosine monophosphate (UcGMP P=0.48) or UAER (P=0.99). During the placebo/ANP arm there was a rise in UFR [13.7+/-2.8 (mean+/-sd) to 25.7+/-7.7 mL/min, P<0.001], UcGMP (60.0+/-36.6 to 160.8+/-118.5 micromol/mmolCr, P=0.045) and UAER [5.13 [2.4-11.6][median (range)] to 71.6 [21.6-175.1] mg/mmolCr, P<0.001]. Pre-treatment with perindopril did not alter the changes in UFR (P=0.63), UcGMP (P=0.46) or UAER (P=0.99) to infusion of ANP, compared with the placebo/ANP arm. CONCLUSION: ANP increases UAER in microalbuminuric patients with Type 2 diabetes and the albuminuric action of ANP is not inhibited by pre-treatment with the ACE inhibitor perindopril.

Adult↗
PubMed2002

Baroregulation of vasopressin release in adipsic diabetes insipidus.

Adipsic diabetes insipidus (ADI) occurs in association with a heterogeneous group of conditions. We report vasopressin (AVP) responses to hypotension in nine patients with ADI and nine controls. Hypertonic saline infusion produced absent thirst (1.7 +/- 1.7 to 1.5 +/- 1.7 cm, P = 0.99) and AVP responses (0.3 +/- 0.1 to 0.4 +/- 0.1 pmol/liter, P = 0.99) in the ADI group, who also drank less than the control group (258 +/- 200 ml vs. 1544 +/- 306 ml, P < 0.001). Intravenous infusion of trimetaphan camsylate produced a fall in mean arterial pressure of 31.6% +/- 8.9% in patients and 29.4% +/- 6.1% in controls. Plasma AVP concentrations rose from 1.4 +/- 0.8 to 340.3 +/- 497.4 pmol/liter (P < 0.001) in the control group. In three patients with craniopharyngioma, there was no rise in plasma AVP concentrations (0.3 +/- 0.1 to 0.3 +/- 0.1 pmol/liter, P = 0.96), but plasma AVP rose significantly in response to hypotension in the other six patients (0.4 +/- 0.2 to 204.5 +/- 223.2 pmol/liter, P < 0.001). We concluded that the AVP responses to hypotension in ADI are heterogeneous and reflect the site of the lesion causing the diabetes insipidus.

Adolescent↗
PubMed2002

Twelve-year experience in the investigation and treatment of paragangliomas.

We report a 12-year laboratory experience in the diagnosis of 37 patients with phaeochromocytoma, one with malignant paraganglioma and one with ganglioneuroblastoma. Surgery was performed in eight different hospitals, which underlines the difficulty of ensuring uniformity of investigations. Of the 37 with phaeochromocytoma, 15 were in the right adrenal gland, 12 were on the left, seven were bilateral and three were extra adrenal. Twenty-three were male and 15 were female; the median age was 36 years. Four of five patients with von Hippel-Lindau disease had bilateral adrenal tumours and four had neurofibromatosis. None had multiple endocrine neoplasia. Using essential hypertensive patients as a reference population, diagnostic sensitivity was 80% for noradrenaline, 54.4% for adrenaline, 19.1% for dopamine, 93.3% for total normetanephrine, 33.3% for total metanephrine, 78.7% for 3-methoxy-4-hydroxymandelic acid (HMMA) and 23.5% for homovanillic acid (HVA). However, if each patient's results were taken as a package, the sensitivities were 100% for noradrenaline, 63.6% for adrenaline, 30.3% for dopamine and 89% for HMMA. Seven recent patients had gene analysis. There were six (15.4%) deaths due directly or indirectly to the paraganglioma. Postoperative blood pressures were normal in 74%. The decrement in catecholamine values post-surgery is shown. Urinary noradrenaline values fell by a mean of 94.5% and the use of urinary noradrenaline as a tumour marker is also demonstrated.

Adrenal Gland Neoplasms↗
PubMed2001

Ligand-induced changes in the Streptomyces lividans TipAL protein imply an alternative mechanism of transcriptional activation for MerR-like proteins.

TipAL is a Streptomyces transcriptional activator assigned to the MerR/SoxR family based both on homology within its putative DNA recognition domain and the fact that its operator binding sites lie within a region of its promoter normally occupied by RNA polymerase. The tipA gene is also independently translated as the C-terminal ligand-binding domain of TipAL (TipAS; residues 111-254). Both TipAS and TipAL share broad recognition specificity for cyclic thiopeptide antibiotics. The molecular mechanism by which TipAL catalyzes prokaryotic transcriptional activation at the tipA promoter (ptipA) in response to thiostrepton was studied using a combination of analytical ultracentrifugation (AU), circular dichroism (CD), optical waveguide lightmode spectroscopy (OWLS; a sensitive in situ binding assay), and mutational analyses. AU showed that TipAL, but not TipAS, was a dimer in solution in the presence or absence of thiostrepton. This indicated that activation of TipAL by thiostrepton was not mediated by changes in multimerization and mapped the dimerization domain to its N-terminal 110 amino acids, presumably within amino acids predicted to form a coil-coil domain (residues 77-109). CD spectra showed that TipAL had more alpha-helical content than TipAS, probably because of the presence of the additional N-terminal region. The helicity of TipAL and TipAS both increased slightly after binding thiostrepton demonstrating conformation changes upon thiostrepton binding. OWLS experiments determined the overall binding constants via measurements of association and dissociation rates for both TipA proteins and RNA polymerase with ptipA. Thiostrepton slightly enhanced the rate of specific association of TipAL with ptipA, but drastically lowered the rate of dissociation from the binding site. TipAL-thiostrepton increased the affinity of RNA polymerase for ptipA more than 10-fold. In conjunction with genetic experiments, we propose that, while there are some similarities, the mechanism by which TipAL activates transcription is distinctly different from the established MerR/SoxR paradigm.

Bacterial Proteins↗
PubMed2001

Artificial aging of phenanthrene in porous silicas using supercritical carbon dioxide.

Expedited artificial aging is described and demonstrated using a novel system that circulates a solution of supercritical carbon dioxide and a hydrophobic organic sorbate (phenanthrene) through a closed loop containing a porous substrate. Unlike traditional methods used to simulate the natural aging process, our approach allows for real-time monitoring of sorption equilibria, and the process is highly accelerated due to the unique physical properties of supercritcal carbon dioxide. The effectiveness of the system to simulate aging was demonstrated with a series of experiments in which three silicas with varying particle and pore sizes were loaded with phenanthrene. Batch aqueous desorption experiments were used to evaluate the extent of the aging process. For the two types of particles containing the largest pores (i.e., mean diameters of 202 and 66 A), 95% and 86%, respectively, of the phenanthrene was released to the aqueous fraction within 3 h. In contrast, only 16% of the phenanthrene was released from particles having a mean pore diameter of 21 A after 24 h. These results were confirmed by the results from an aqueous column desorption experiment. Confounding factors that might contribute to slow aqueous desorption such as the hydration state of the particles' surfaces, the chemical form of the loaded phenanthrene, and the organic carbon content were investigated and/or normalized for all three particle types. Consequently, we were able to attribute the slow desorption behavior and the presence of the resistant fraction in the 21 A silica to pore effects. With properly designed experiments, the results of this study suggest that the supercritical fluid system could be extended to the study of contaminant aging and bioavailability in natural soils and sediments.

Adsorption↗
PubMed2001

Pleiotropic functions of a Streptomyces pristinaespiralis autoregulator receptor in development, antibiotic biosynthesis, and expression of a superoxide dismutase.

In Streptomyces, a family of related butyrolactones and their corresponding receptor proteins serve as quorum-sensing systems that can activate morphological development and antibiotic biosynthesis. Streptomyces pristinaespiralis contains a gene cluster encoding enzymes and regulatory proteins for the biosynthesis of pristinamycin, a clinically important streptogramin antibiotic complex. One of these proteins, PapR1, belongs to a well known family of Streptomyces antibiotic regulatory proteins. Gel shift assays using crude cytoplasmic extracts detected SpbR, a developmentally regulated protein that bound to the papR1 promoter. SpbR was purified, and its gene was cloned using reverse genetics. spbR encoded a 25-kDa protein similar to Streptomyces autoregulatory proteins of the butyrolactone receptor family, including scbR from Streptomyces coelicolor. In Escherichia coli, purified SpbR and ScbR produced bound sequences immediately upstream of papR1, spbR, and scbR. SpbR DNA-binding activity was inhibited by an extracellular metabolite with chromatographic properties similar to those of the well known gamma-butyrolactone signaling compounds. DNase I protection assays mapped the SpbR-binding site in the papR1 promoter to a sequence homologous to other known butyrolactone autoregulatory elements. A nucleotide data base search showed that these binding motifs were primarily located upstream of genes encoding Streptomyces antibiotic regulatory proteins and butyrolactone receptors in various Streptomyces species. Disruption of the spbR gene in S. pristinaespiralis resulted in severe defects in growth, morphological differentiation, pristinamycin biosynthesis, and expression of a secreted superoxide dismutase.

Amino Acid Sequence↗
PubMed2001

Novel pristinamycin-responsive expression systems for plant cells.

Novel gene regulation systems were designed for plant cells responsive to the streptogramin antibiotic pristinamycin. The pristinamycin-repressible plant gene regulation concept (PIPpOFF) is based on a transcriptional activator (PIT) which consists of the Pip protein, the repressor of the pristinamycin resistance operon of Streptomyces coelicolor, fused to the VP16 transactivation domain of the Herpes simplex virus. PIT mediates pristinamycin-repressible activation of a synthetic plant promoter (P(pPIR)) in tobacco cells consisting of a nine Pip-binding site-containing artificial operator (PIR3) placed upstream of a TATA-box derived from the cauliflower mosaic virus 35S promoter (P(CaMV35S)). Pristinamycin interferes with induction by negatively regulating the DNA-binding capacity of the Pip moiety of PIT. A second, streptogramin-inducible plant gene regulation system (PIPpON) was constructed by combining Pip expression with a plant-specific pristinamycin-inducible promoter (P(pPIRON)). P(pPIRON) consists of a PIR3 module cloned downstream of the strong constitutive plant promoter P(CaMV35S). As in the native Streptomyces configuration, Pip binds to its cognate sequence within P(pPIRON) in the absence of regulating antibiotic and silences the chimeric plant promoter. Upon addition of pristinamycin, Pip is released from the PIR3 operator and full P(CaMV35S)-driven expression of desired plant genes is induced. The PIPpOFF and PIPpON systems performed well in Nicotiana tabacum suspension cultures and promise to provide an attractive extension of existing plant gene regulation technology for basic plant research or biopharmaceutical manufacturing using plant tissue culture.

Amino Acid Sequence↗
PubMed2001

A fluorescence spectroscopic study of phenanthrene sorption on porous silica.

Fluorescence spectroscopic characteristics of sorbed phenanthrene in porous silica provide information about its chemical state such as monomer vs dimer or higher aggregates, as well as a basis for high sensitivity detection. In this study, the chemical state and distribution of phenanthrene sorbed in two types of porous silica particles, mesoporous silica (365 microns particle diameter, 150 A average pore diameter) and microporous silica (custom synthethized, 1 micron particle diameter, 20 A pore diameter), is determined by fluorescence spectroscopy, fluorescence lifetime measurements, and scanning two-photon excitation fluorescence profiling. From the characteristic fluorescence emission spectra, it is found that at loading levels of < or = 4.7 mg/g (phenanthrene/silica) phenanthrene exists as monomers in both meso- and microporous silica particles for phenanthrene loaded from super critical CO2 (SCF). Two-photon excitation fluorescence intensity distribution profiles indicate that for the mesoporous silica particles phenanthrene is adsorbed throughout the entire silica particle. Introduction of water into phenanthrene-loaded mesoporous silica particles causes instantaneous conversion of phenanthrene from monomer to crystalline form at phenantherene loading levels > or = 4.7 micrograms/g due to hydration of the silica surface. In this process, sorption of water molecules expels phenanthrene from the surface sorption sites and causes localized phenanthrene concentration beyond its solubility limit, resulting in crystallization. In comparison this fast conversion is not observed for phenanthrene-loaded microporous silica particles that show extremely slow conversion even for phenanthrene loading levels as high as 4.7 mg/g. This difference is interpreted as reflecting hindered diffusion of phenanthrene in the nearly monodispersed micropores with pore sizes close to the molecular diameter of phenanthrene.

Absorption↗
PubMed2001

A transcriptional regulator of a pristinamycin resistance gene in Streptomyces coelicolor.

Pip is a pristinamycin-induced transcriptional regulator protein detected in many Streptomyces species by its ability to specifically bind sequence motifs within the promoter of a Streptomyces pristinaespiralis multidrug resistance gene (ptr). To investigate the possible role of Pip in regulating multidrug resistance, it was purified from a genetically characterized species, Streptomyces coelicolor, utilizing an affinity matrix of the ptr promoter conjugated to magnetic beads. Reverse genetics identified the corresponding locus and confirmed that it encoded Pip, a protein belonging to the TetR family of procaryotic transcriptional repressors. Pip binding motifs were located upstream of the adjacent gene pep, encoding a major facilitator antiporter homologous to ptr. In vivo analysis of antibiotic susceptibility profiles demonstrated that pep conferred elevated levels of resistance only to pristinamycin I (PI), a streptogramin B antibiotic having clinical importance. Purified recombinant Pip was a dimer (in the presence or absence of PI) and displayed a high affinity for its palindromic binding motifs within the ptr promoter and the upstream region of pep. The Pip/ptr promoter complex was dissociated by PI but not by any of the other nonstreptogramin antibiotics that were described previously as transcriptional inducers. These procaryotic regulatory elements served as the basis for the development of systems allowing repression or induction of cloned genes in mammalian and plant cells in response to streptogramin antibiotics (including pristinamycin, virginiamycin, and Synercid(R)).

Anti-Bacterial Agents↗