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G Nicholls

Publications and source records attributed to G Nicholls.

At least 19 recordsLinked to original sources
PubMed2005

Impact of end-product inhibition on the determination of in vitro metabolic clearance.

End-product inhibition was explored as a mechanism for the lower clearance determination obtained from microsomes compared with hepatocytes. Triazolam, diazepam and phenytoin microsomal substrate depletion was reduced by 23, 34 and 39%, respectively, when incubated with their primary metabolites. Ki values of 28+/-6 and 11+/-1 microM were obtained when 4'-hydroxydiazepam and p-hydroxyphenytoin where incubated with diazepam and phenytoin, respectively. Alamethicin (a glucuronidation activator) was unsuccessful in alleviating these effects. IC50 values of 17, 32 and 18 microM for phenytoin and 83, 110 and 97 microM for diazepam were observed with salicylamide- (a glucuronidation inhibitor) treated hepatocytes, control hepatocytes and microsomes, respectively, when incubated with their primary metabolites. These differences suggest that metabolite concentrations in the vicinity of the enzyme are lower in hepatocytes compared with microsomes, reducing the likelihood of end-product inhibition in the former system. In conclusion, end-product inhibition may be more prominent in microsomes (in particular for substrate depletion assays where metabolism tends to be more extensive); results suggest that this phenomenon may contribute to the observed variations in metabolism characteristics and intrinsic clearance (CLint) between hepatocytes and microsomes.

Alamethicin↗
PubMed2004

Surgical risk factors for Hickman catheter sepsis: a prospective study.

Catheter-related sepsis (CRS) is a major cause of morbidity in patients receiving chemotherapy and prolonged parenteral nutrition. To determine whether avoiding emergency insertions by using a planned elective list and adopting a 'no-touch' technique has a role in reducing CRS, all cuffed central venous catheters inserted by the open method between 1999 and 2000 were prospectively followed for a total duration of 12 months. The incidence of early sepsis (within 30 catheter days) that could be attributed to surgical factors was studied. CRS was defined as the presence of any two of the following: (1) signs of clinical sepsis without an obvious focus; (2) positive cultures in blood obtained from the catheter; and (3) clinical improvement following removal. A total of 146 catheters were inserted in 130 patients; 15 had a second and 1 had a third catheter inserted. Early CRS was encountered in 13 cases (9%); 95 catheters were inserted on an elective list and 51 on an emergency basis. The distributions of age, sex, number of lumens, neutrophil count, and underlying diagnosis were similar between the groups. There was no significant difference (P = 1) between elective (9/95) and emergency (4/51) insertions. A total of 47 catheters were inserted by the 'no-touch' technique and 48 by the manual technique. There was no significant difference in early sepsis (P = 0.7) between the two techniques (6/47 vs 3/48). Thus avoiding emergency insertion or adopting a 'no-touch' technique does not reduce early CRS. Larger prospective studies are warranted to identify surgical risk factors.

Catheterization, Central Venous↗
PubMed2001

Endopyelotomy in the symptomatic older child.

OBJECTIVE: To evaluate the results of endopyelotomy in children, an established method in adult practice as a treatment for pelvi-ureteric junction (PUJ) obstruction. PATIENTS AND METHODS: Endopyelotomies undertaken between 1992 and 1999 by one surgeon in an established endourology unit were reviewed retrospectively. Children aged > 5 years presenting with pain and obstruction on isotope renography were selected for endopyelotomy. Patients with crossing vessels detectable on spiral computed tomography were treated by open pyeloplasty. Access to the renal pelvis was provided by a uroradiologist. Endopyelotomy was carried out through an Amplatz sheath of (median) 26 F. After applying traction to invaginate the PUJ an incision was made postero-laterally using electrocautery via an 11 F paediatric resectoscope. Stenting was maintained for 6 weeks. In all, 13 patients (median age 10 years, range 5-14) were treated; two had associated calculi. RESULTS: The symptoms resolved and the obstruction was relieved in only six patients, with a median (range) follow-up of 50 (26-68) months. The seven patients in whom endopyelotomy failed, as indicated by persistent pain, proceeded to open pyeloplasty at a median (range) of 4 (1.3-79) months. Of these, two had presented with associated multiple calculi and significant hydronephrosis (one with an associated duplex system) and three had crossing lower pole vessels at open operation. One developed a urinoma after the original endopyelotomy and one had a retained stent fragment removed at the time of pyeloplasty. CONCLUSIONS: Endopyelotomy in the symptomatic child requires a careful preoperative evaluation. Crossing lower pole vessels warrant an open pyeloplasty.

Adolescent↗
PubMed2001

C-type natriuretic peptide expression in olfactory regions of rat brain is modulated by acute water deprivation, salt loading and central angiotensin II.

To elucidate the central role of c-type natriuretic peptide (CNP), levels of CNP mRNA in control rat brain were compared with levels following acute water deprivation, salt loading and central administration of angiotensin II (AII), using Northern blot and in situ hybridisation. Rats with water deprivation (WD) had no access to water for 48 h, rats with salt loading (SL) had access to 2% saline for 48 h, and control rats had free access to water. Both WD and SL significantly raised plasma sodium (Na). Levels of CNP mRNA in olfactory regions were significantly decreased in WD and increased in SL. In the medulla, WD and SL both increased CNP mRNA, but levels of CNP mRNA elsewhere in the brain were not significantly altered. Intracerebroventricular AII (500 ng) increased water intake, and induced a significant increase in CNP expression at 4 h in olfactory regions, but not in other brain sites. In summary, CNP expression is regulated in olfactory regions of the rat brain in response to acute challenges to water and salt balance and by central AII.

Angiotensin II↗
PubMed2000

Recipient FK506 pretreatment regimens in rat small bowel transplantation: allograft survival, function, and systemic infection.

PURPOSE: Successful small bowel transplantation requires effective immunosuppression that preserves intestinal function but avoids opportunistic infection. This study aims to evaluate FK506 as a single immunosuppressant in different pretreatment regimens in a rat high responder strain combination. METHODS: Lewis --> DA rat heterotopic small bowel transplantation was performed. Studied groups were (1) untreated control, n = 12; (2) FK-1, n = 8; (3) FK-3, n = 8. FK506 (2 mg/kg/d, intramuscularly) was given to the recipients for 1 day (FK-1) and 3 days (FK-3) before small bowel transplantation, followed by 2 weeks of subtherapeutic treatment (0.3 mg/kg/d, intramuscularly) after small bowel transplantation. Syngeneic small bowel transplantation also was performed (n = 8). FK blood levels, maltose absorption test, histology, and bacteriology were performed at different postoperative days. RESULTS: Allograft survival was prolonged significantly with FK pretreatment, being more so in FK-3 group (FK-1, 22.2 +/- 1.5 d; FK-3, 40.7 +/- 14.1 d; control, 6.6 +/- 0.8 d; P< .01). In the first postoperative week, FK blood level was significantly higher in FK-3 group (19.8 +/- 1.5 ng/mL) than in FK-1 group (5.0 +/- 0.4 ng/mL; P < .05). There was no evidence of systemic infection in either FK-treated group. For maltose absorption, control allograft was abnormal on day 7 correlating to severely damaged intestinal architecture. In contrast, FK-treated allografts showed well-protected intestinal structure and normal absorption on days 7 and 21. CONCLUSION: High FK506 blood levels in the first postoperative week, achieved with FK pretreatment, prolonged intestinal allograft survival and preserved intestinal structure and function without allowing systemic infection.

Animals↗
PubMed1999

The amino terminal regions of proBNP and proANP oligomerise through leucine zipper-like coiled-coil motifs.

We provide the first report of unique leucine zipper-like coiled-coil sequence motifs at the amino terminus (N-) of proBrain Natriuretic Peptide (proBNP) and proAtrial Natriuretic Peptide (proANP). These motifs were highly conserved across most of the known natriuretic peptide sequences from different species. Consistent with computer based modelling predictions, size exclusion (SE) chromatography analysis confirmed human and ovine N-BNP, N-ANP and human proBNP in plasma extracts to elute as high molecular weight oligomers. Synthetic model peptides corresponding to the proposed leucine zipper-like coiled-coil regions of proBNP, proANP and their related N-terminal peptides were shown to be sufficient to induce oligomerisation when assessed on size exclusion HPLC. To our knowledge, this is the first report of circulating peptides that oligomerise through leucine zipper-like coiled-coil motifs, and adds a new dimension to the field of vasoactive peptide research.

Amino Acid Sequence↗
PubMed1999

Implications of antenatal diagnosis of small-intestinal atresia in the 1990s.

To assess the prevalence of antenatal diagnosis of small-intestinal atresias (SIA) in the modern era and determine its effect on management and outcome, the records of neonates admitted to a single institution in 1991-1996 with a diagnosis of SIA were reviewed. Duodenal atresia, atresias complicating meconium ileus, and those associated with gastroschisis were excluded. Of 14 neonates with SIA, 10 had jejunal atresia (JA) (Grosfeld type I, n = 1; type II, n = 2; type IIIa, n = 3; type IIIb [apple peel], n = 3; type IV, n = 1) and 4 had ileal atresia (IA) (type II, n = 1; type IIIa, n = 3). Antenatal diagnosis was made in 4 neonates (overall rate = 28%), including all 3 type IIIb JA, and 1 type II JA. None of the IAs were diagnosed antenatally. There were 2 deaths, both in patients with high JAs with less than 10 cm viable bowel. Only 1 of these was antenatally diagnosed. The median (range) times to full enteral feeding were 20 days (17-22) for antenatally-diagnosed JA, 14 days (11-26) for other JAs, and 8 days (6-15) for IAs. Antenatal diagnosis of SIA thus remains relatively infrequent (less than one-third of cases). When an antenatal diagnosis is made, the atresia is more likely to be proximal in location, requiring intensive and prolonged postnatal treatment. Provided a reasonable length of bowel remains, the outcome of SIA, whether antenatally diagnosed or not, is favorable.

Female↗
PubMed1999

Bench surgery with autotransplantation for bilateral synchronous Wilms' tumor: a report of three cases.

The surgical management of bilateral synchronous nephroblastoma remains controversial. The authors describe three cases treated using ex vivo tumor dissection followed by autotransplantation in an attempt to preserve functioning renal tissue. Two children are alive and tumor free with adequate renal function at 30 months and 3 years, respectively. One died from tumor recurrence with metastases 9 months after surgery. This technique is an acceptable alternative to bilateral nephrectomy followed by transplantation.

Humans↗
PubMed1999

Intrinsic duodenal obstruction: trends in management and outcome over 45 years (1951-1995) with relevance to prenatal counselling.

OBJECTIVE: To investigate the incidence of associated anomalies and document changes and progress in the management and outcome of intrinsic duodenal obstruction (atresia or stenosis) in a large series over a long time period with a view to providing comprehensive data for prenatal counselling. DESIGN: A retrospective casenote review. SETTING: A quaternary referral centre for paediatric and neonatal surgery. POPULATION: Two hundred and seventy-five infants born with duodenal obstruction between 1951 and 1995. METHODS: For analysis of management and outcome data, the series was divided into three groups, each admitted over 15 year periods: Group A, 1951-1965; Group B, 1966-1980; Group C, 1981-1995. MAIN OUTCOME MEASURES: Primary: associated anomalies, complication rates and survival. Secondary: age at diagnosis, duration of hospital stay. RESULTS: There were 136 males and 139 females. Seventeen of 30 cases (57%) presenting between 1991 and 1995 were diagnosed prenatally on ultrasound scan. The median age at diagnosis for atresia was 3.5 days (Group A); 2.2 days (Group B) and 1.8 days (Group C). The median age at diagnosis for incomplete obstruction was five days. Associated anomalies included Down's syndrome (n = 82, 30%); Down's plus cardiac malformation (n = 38, 14%); isolated cardiac (n = 64, 23%); and gastrointestinal problems (n = 116, 42%). Overall complication rates fell from 51% (Group A) to 18% (Group C) and survival increased from 51% to 95% . Median hospital stay also decreased from 35 days to 18 days. CONCLUSIONS: These data confirm a progressive improvement in the outcome of intrinsic duodenal obstruction over the past 45 years. It is important to note that they only relate to infants born with duodenal atresia and do not take into account possible 'hidden' mortality resulting from spontaneous abortion or termination.

Abnormalities, Multiple↗
PubMed1998

Expression of stressful experiences through writing: effects of a self-regulation manipulation for pessimists and optimists.

This study assessed the effectiveness of a writing task designed to foster self-regulatory coping with stressful experiences to reduce medical clinic visits and to promote adjustment. Students entering college (N = 122) who were classified as optimists or pessimists by using a dispositional optimism measure participated in a self-regulation task (expressing thoughts and feelings about entering college and then formulating coping plans), a disclosure task (expressing thoughts and feelings only), or a control task (writing about trivial topics) for 3 weekly writing sessions. Among optimists, both the self-regulation task and the disclosure task reduced illness-related clinic visits during the following month; among pessimists, only the self-regulation task reduced clinic visits. In general, the self-regulation task beneficially affected mood state and college adjustment whereas the disclosure task increased grade point averages.

Achievement↗
PubMed1998

Anatomical correction of the exstrophy-epispadias complex: analysis of 34 patients.

OBJECTIVE: To evaluate the surgical procedures required for anatomical reconstruction of the bladder and penis in the exstrophy-epispadias complex. PATIENTS AND METHODS: All primary exstrophy-epispadias repairs carried out by one surgeon between 1987 and 1997 were reviewed. Bladder closure consisted of full extraperitoneal mobilization, transpositional omphaloplasty, drainage with ureteric and urethral catheters and immobilization with a 'frog-leg' plaster-cast or 'mermaid' dressings. Osteotomies were always performed when bladder closure was attempted after 37 h of age. Before 1990 the osteotomies were posterior vertical iliac (one patient) and subsequently anterior oblique iliac (10 patients). Pre-peritoneal herniotomies, in the absence of a clinical hernia, were included in the primary procedure after 1992. A modified Cantwell technique was used for epispadias repair and this was undertaken at a median of 16 months after bladder closure (range 6-30). RESULTS: Thirty-four patients (27 male) were reviewed; one patient had a chromosomal abnormality, a deletion in the short arm of chromosome 4. The male infants required a median of four procedures (range 2-5) for bladder closure, epispadias reconstruction and herniotomies, while the females needed a median of two (range 2-5). Complete bladder dehiscence, requiring re-closure with osteotomies, occurred in three cases (9%, two male). There were no dehiscences in the primary osteotomy group. Fistulae after epispadias repair occurred in four patients (17%). The bladder capacity increased to > 60 mL in 10 of 15 males by 36 months after epispadias repair. Only two of seven female infants attained a capacity of > 60 mL. Of the 15 infants who did not undergo herniotomy at primary closure, 13 subsequently developed inguinal hernias (one uni- and 11 bilateral) with incarceration occurring in two. Twelve infants underwent herniotomy at primary closure and six developed subsequent hernias (two uni- and four bilateral; P = 0.05) with documented incarceration in two. CONCLUSIONS: Anatomical correction of the exstrophy-epispadias complex remains challenging, but can be achieved with complication rates of < 20% for each stage. Bladder volumes large enough to permit adequate bladder neck reconstruction can be anticipated after epispadias repair in a large proportion of male infants, but remains small in female infants with low outlet resistance. Inguinal herniotomy at the time of bladder closure significantly reduces the incidence of subsequent herniation, which nevertheless remains high.

Bladder Exstrophy↗
PubMed1998

Angiotensinogen T235 and ACE insertion/deletion polymorphisms associated with albuminuria in Chinese type 2 diabetic patients.

OBJECTIVE: Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of diabetic proteinuria. Ethnic differences in the frequencies of these genotypes have also been reported. To date, most of these studies have been performed in white and Japanese populations. In this study, we examined the associations between albuminuria and RAS genetic polymorphisms in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a case-control study, the ACE insertion/deletion (I/D) gene, the angiotensinogen (AGT) gene (M235T), and the angiotensin II (AII) type 1 receptor gene (AT1 A1166C) were examined in 110 Chinese type 2 diabetic patients. Increased urinary albumin excretion (UAE) was defined as > or = 30 mg/day on at least two occasions during a 6-week study period. RESULTS: Compared with whites, there were high frequencies of the AGT TT genotype in Chinese control subjects (120/183 = 70%) and type 2 diabetic patients (74/110 = 67%). The frequencies of the MM genotype were 5 and 3%, respectively, and those of the ACE DD genotype were 13 and 10%, respectively. Although 9% of subjects carried the C allele, the AT1 CC genotype was not found in either group. Chinese type 2 diabetic patients with increased albuminuria (n = 56) had higher systolic blood pressure (160 +/- 26 mmHg vs 145 +/- 27 mmHg, P < 0.001) than the normoalbuminuric patients (n = 54). Both the AGT TT genotype (78.6% [44/56] vs. 55.6% [30/54], odds ratio [OR]: 3.0 [1.3-6.8]) and the T allele (88% [99/112] vs. 77% [83/108], OR: 2.5 [1.3-5.4]) were associated with an increased risk of albuminuria. Patients with the AGT TT genotype (n = 74) had higher 24-h UAE than those with the MT or MM genotypes (n = 36) (median: 37.8 mg/day vs. 17.8 mg/day, P < 0.01). This association remained significant in patients with normotension (56 mg/day [n = 19] for patients with the TT genotype vs. 22 mg/day [n = 14] for those with the MT/MM genotype, P = 0.03). The D allele carriers (DD or DI, n = 61) had higher serum ACE activities (75.5 +/- 29 U/l vs. 60.5 +/- 36.3 U/l, P < 0.01) than the noncarriers (II genotype). The median 24-h UAE also tended to be higher in the D allele carriers (38.9 mg/day vs. 21.4 mg/day, P = 0.07). The lowest UAE was observed in patients with the MM/MT/II genotype (16.3 mg/day [n = 18]) and the highest, in patients with the TT/DD/DI genotype (52.3 mg/day [n = 43]). No association was found between the TT genotype or D allele and hypertension. CONCLUSIONS: The high frequencies of the TT genotype and T allele in Chinese populations may contribute to the high prevalence of albuminuria in patients with type 2 diabetes. The possibility of synergism between the AGT TT genotype and the ACE D allele should also be explored.

Adult↗
PubMed1997

Cisapride reduces neonatal postoperative ileus: randomised placebo controlled trial.

AIM: To assess the efficacy of cisapride in reducing ileus persisting to the tenth postoperative day after neonatal abdominal surgery. METHODS: A prospective, randomised, double blind trial comparing rectal cisapride (1.4-2.3 mg/kg/day) with placebo over seven days was undertaken in 33 neonates. RESULTS: Seven of 12 (58%) patients receiving placebo and eight of 11 (73%) receiving cisapride achieved a first sustained feed during treatment. Of those receiving cisapride, the first sustained feed occurred at 2.3 days (SEM 0.6) compared with 4.7 days (SEM 0.8) with placebo. By the seventh day the mean daily net enteral balance was 69 (SEM 18) ml/kg in the cisapride subgroup and 17 (SEM 8) ml/kg for those receiving placebo. Stool was passed on 6.3 (SEM 0.4) treatment days in the cisapride subgroup compared with 4.1 (SEM 1.0) treatment days in the placebo subgroup. CONCLUSION: Cisapride is effective in neonates with a prolonged ileus after abdominal surgery.

Administration, Rectal↗