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Biomedical subjects

G M Cooper

Publications and source records attributed to G M Cooper.

At least 37 records · Page 2Linked to original sources
PubMed2000

National obstetric anaesthetic practice in the UK 1997/1998.

In the United Kingdom, the Royal College of Obstetricians and Gynaecologists requires maternity units recognised for training to complete annual statistical returns. Analysis of these data revealed that anaesthetists were directly involved in more than 251 000 procedures in the peripartum period in 1997/1998. There had been an increase in the number of women delivered by Caesarean section (18. 5% of all deliveries) compared with previous reports. The proportion of Caesarean sections performed under regional anaesthesia had increased for both elective and emergency Caesarean section deliveries (85.5% and 70.2%, respectively). For pain relief in labour, there had been neither an increase nor a decrease in the uptake of regional analgesia (23.6%). There were limited training opportunities for anaesthetists in general anaesthesia for Caesarean section and for obstetricians in vaginal breech delivery. The known admissions to intensive care units equated to over 100 women per month in the United Kingdom requiring intensive care as a result of childbirth.

Analgesia, Obstetrical↗
PubMed2000

Age-related changes in intracranial pressure in rabbits with uncorrected familial coronal suture synostosis.

OBJECTIVE: Chronic, elevated intracranial pressure (ICP) in craniosynostotic infants may result in ocular and neurocapsular problems; however, not all infants exhibit elevated ICP. Clinical ICP studies are further confounded by small and heterogeneic samples, multiple-suture involvement, and varying surgical management protocols. The present study was designed to describe longitudinal changes in ICP in a large, homogenous sample of rabbits with uncorrected familial, nonsyndromic coronal suture synostosis. METHODS: Ninety-one rabbits were divided into four groups: (1) normal rabbits (n = 28), (2) rabbits with delayed-onset coronal suture synostosis (DOCS; n = 25), (3) rabbits with unilateral coronal suture synostosis (UCS; n = 12), and (4) rabbits with bilateral coronal suture synostosis (BCS; n = 26). ICP was measured at 24 and 42 days of age using a Codman epidural microtransducer. RESULTS: Rabbits with BCS had a significantly (p < .05) higher mean ICP at 25 days of age than rabbits in the other three groups by approximately 146%. However, by 42 days of age, mean ICP in normal control rabbits and rabbits with DOCS was significantly (p < .01) increased compared with their mean ICP values seen at 25 days of age, while mean ICP in BCS rabbits significantly (p < .01) decreased (by 32%) over the same time period. ICP in rabbits with UCS was between that seen in normal control rabbits and rabbits with BCS and did not significantly (p > .05) change over time. CONCLUSIONS: These findings suggest that the degree of suture involvement may be related to early increases in ICP. Possible multifactorial explanations for intracranial decompression and compensation in the craniosynostotic rabbit model are discussed.

Aging↗
PubMed1999

Identification of COUP-TF as a transcriptional repressor of the c-mos proto-oncogene.

The c-mos proto-oncogene is specifically expressed in the male and female germ cells of the mouse and other vertebrates. We previously identified a 15-base pair sequence element (B2) as the binding site of a candidate repressor of c-mos transcription in somatic cells. In the present study, we used the yeast one-hybrid system to isolate HeLa cell cDNAs encoding proteins that specifically bound to the c-mos B2 element. Nucleotide sequencing identified several of the clones isolated in this screen as the orphan nuclear receptors COUP-TFI and COUP-TFII. A COUP-TF-binding site was then identified within the B2 sequence. Complexes formed between purified COUP-TFs and the c-mos B2 probe comigrated in electrophoretic mobility shift assays with those formed using whole nuclear extracts of NIH 3T3 or HeLa cells. Moreover, the complexes formed with NIH 3T3 nuclear extracts and B2 probe were supershifted with antibody against COUP-TF, identifying COUP-TF as the candidate repressor previously detected in these somatic cell extracts. Substitution of a consensus COUP-TF-binding site for the c-mos negative regulatory element suppressed expression from the c-mos promoter in transfected somatic cells, demonstrating the functional activity of COUP-TF as a repressor of c-mos transcription.

3T3 Cells↗
PubMed1999

Cardiac arrhythmias in children during outpatient general anaesthesia for dentistry: a prospective randomised trial.

BACKGROUND: Deaths in children associated with outpatient general dental anaesthesia may be attributable to sudden cardiovascular collapse precipitated by ventricular arrhythmias. A causal link between halothane anaesthesia, ventricular arrhythmias, and deaths has been suggested. We did a prospective, randomised trial to investigate the frequency and character of arrhythmias during anaesthesia with halothane and the alternative anaesthetic agent, sevoflurane. METHODS: 150 children, aged 3-15 years, who needed dental extraction under general anaesthesia were randomly assigned sevoflurane or halothane supplementation of 66% nitrous oxide in oxygen with spontaneous ventilation. The halothane group (n=50) received halothane introduced in 0.75% increments, every two to three breaths, to a maximum of 3.0%, with maintenance at 1.5%. The incremental sevoflurane group (n=50) received sevoflurane introduced in 2% increments increased to a maximum of 8%, with maintenance at 4%. The 8% sevoflurane group (n=50) received sevoflurane introduced at 8%, with maintenance at 4%. FINDINGS: 24 (48%) children receiving halothane had arrhythmias compared with four (8%) receiving incremental sevoflurane (difference 40% [95% Ci for differences 24-56] p<0.0001), and eight (16%) receiving 8% sevoflurane (difference 32% [15-50] p=0.0013). Halothane-associated arrhythmias occurred during dental extraction or emergence and were mainly ventricular. Six (12%) children in the halothane group had ventricular tachycardia. The methods of sevoflurane administration did not differ significantly for the frequency of arrhythmias (p=0.357). Sevoflurane-associated arrhythmias were mainly single supraventricular ectopic beats. INTERPRETATION: There was a strong association between halothane and ventricular arrhythmias, especially ventricular tachycardia. The use of sevoflurane in preference to halothane could contribute to a decline in morbidity and mortality associated with dental anaesthesia.

Adolescent↗
PubMed1999

Coronal suture response to distraction osteogenesis in rabbits with delayed-onset craniosynostosis.

Recent studies have identified a subpopulation of persons with craniosynostosis who exhibit progressive or delayed-onset synostosis and mild cranial vault deformities. These persons may be good candidates for nonextirpation distraction osteogenesis. The present studies were designed to determine force-displacement parameters and assess the effects of distraction osteogenesis on coronal suture growth and morphologic characteristics in a rabbit model with congenital, delayed-onset craniosynostosis. Data were collected from a total of 178 rabbits: 71 normal controls; 16 normal controls with distraction; 72 with delayed-onset coronal suture synostosis; and 19 with delayed-onset coronal suture synostosis and distraction. At 10 days of age, all rabbits had amalgam markers placed on both sides of the coronal suture. In the force-displacement study, force-displacement distractors were placed across the coronal suture and distracted acutely for 1.0 mm at 42 days of age. Force-displacement curves for the coronal suture were best described by a third-order polynomial regression equation for both normal and synostosed groups. Significant differences (P < 0.05) were found in the mean force necessary to distract a normal suture 1 mm in distance (13.72 kg) compared with a suture with delayed-onset synostosis (48.39 kg). A significant (P < 0.05) relationship was also found between the extent of synostosis and the distractive force in rabbits with delayed-onset synostosis. In the distraction study, internal distractors were fixed across the coronal suture at 25 days of age and percutaneously and intermittently activated at an average of 0.11 mm/day for 42 days (4.54 mm total). Serial radiographs were taken at 10, 25, 42, and 84 days of age. Results revealed that rabbits with delayed-onset synostosis and distraction had significantly (P < 0.01) more coronal suture growth rates compared with rabbits with delayed-onset synostosis and no distraction. Coronal sutures were harvested at 84 days of age for qualitative histologic examination. Normal, distracted coronal sutures showed widened sutural ligaments and thin, active osteogenic fronts. In contrast, distracted coronal sutures from rabbits with delayed-onset synostosis showed narrowed sutural ligaments, thickened and blunt osteogenic fronts, and increased collagen and bony matrix deposition compared with controls. Results suggest that distraction osteogenesis without corticotomy may be a treatment alternative in persons with progressive, delayed-onset synostosis. However, these preliminary data also suggest that distractive forces may accelerate or stimulate osteogenesis differentially in persons with craniosynostosis, possibly through an underlying genetic disorder of bone and cytokine regulation. These differential osteogenic responses to distraction, if validated clinically, will need to be taken into account when planning distraction rate and rhythm protocols for patients with craniosynostosis.

Age of Onset↗
PubMed1999

Increased intracranial pressure after coronal suturectomy in craniosynostotic rabbits.

It has been suggested that the complications associated with intracranial hypertension in craniosynostotic infants may be managed with surgical release of the synostosed sutures. However, both postoperative increases and decreases in intracranial pressure (ICP) have been reported in heterogeneous samples of infants with syndromic and nonsyndromic craniosynostoses. The present study was designed to describe longitudinal changes in ICP in a homogeneous sample of rabbits with uncorrected and corrected familial coronal suture synostosis and compare them with age-matched normal control rabbits. Fifty-three rabbits were divided into three groups: normal rabbits (n = 28), rabbits with uncorrected bilateral coronal suture synostosis (n = 9), and rabbits with bilateral coronal suture synostosis with coronal suturectomy at 25 days of age (n = 16). ICP was measured at 25 and 42 days of age using a Codman epidural microtransducer. Results revealed that rabbits with uncorrected craniosynostosis had significantly (P < 0.05) higher ICP at 25 days of age than normal control rabbits by approximately 86%. However, by 42 days of age, ICP in normal rabbits increased by 75%, whereas ICP in rabbits with uncorrected craniosynostosis decreased by 69% over the same time. Synostotic rabbits with coronal suturectomy showed a 50% decrease in ICP immediately after surgical release and then followed the normal, age-related ICP pattern, which significantly increased by 75% at 42 days of age. Results suggest that, in the rabbit model, the postsuturectomy rise in ICP may simply be normal, age-related changes, although a longer follow-up will be needed to determine the recurrence of pathological ICP. Possible multifactorial explanations for intracranial decompression and compensation in the craniosynostotic rabbit model are also discussed.

Analysis of Variance↗
PubMed1999

B-Raf inhibits programmed cell death downstream of cytochrome c release from mitochondria by activating the MEK/Erk pathway.

Growth factor-dependent kinases, such as phosphatidylinositol 3-kinase (PI 3-kinase) and Raf kinases, have been implicated in the suppression of apoptosis. We have recently established Rat-1 fibroblast cell lines overexpressing B-Raf, leading to activation of the MEK/Erk mitogen-activated protein kinase pathway. Overexpression of B-Raf confers resistance to apoptosis induced by growth factor withdrawal or PI 3-kinase inhibition. This is accompanied by constitutive activation of Erk without effects on the PI 3-kinase/Akt pathway. The activity of MEK is essential for cell survival mediated by B-Raf overexpression, since either treatment with the specific MEK inhibitor PD98059 or expression of a dominant inhibitory MEK mutant blocks the antiapoptotic activity of B-Raf. Activation of MEK is not only necessary but also sufficient for cell survival because overexpression of constitutively activated MEK, Ras, or Raf-1, like B-Raf, prevents apoptosis after growth factor deprivation. Overexpression of B-Raf did not interfere with the release of cytochrome c from mitochondria after growth factor deprivation. However, the addition of cytochrome c to cytosols of cells overexpressing B-Raf failed to induce caspase activation. It thus appears that the B-Raf/MEK/Erk pathway confers protection against apoptosis at the level of cytosolic caspase activation, downstream of the release of cytochrome c from mitochondria.

Animals↗
PubMed1999

Brain growth rates in craniosynostotic rabbits.

OBJECTIVE: It has been suggested that abnormal brain morphology or growth rates may be a primary causal factor of craniosynostosis due, in part, to a lack of normal growth stretch and tension at the sutural margins. The purpose of the present study was to quantify cerebral hemisphere morphology and growth in a rabbit model of nonsyndromic coronal suture synostosis to determine whether cerebral dysmorphology is primary or secondary to synostosis in this model. DESIGN: Fifty-seven brains (114 hemispheres) were examined from 40 normal control rabbits and 17 rabbits with bilateral coronal suture synostosis ranging in age from 25 to 450 days postconception (synostosis occurs at approximately 23 days postconception in this model). The calvariae were removed, the brains were fixed in 10% paraformaldehyde, and in situ bilateral measurements of cerebral hemisphere length and cerebral hemisphere width were obtained using a Wild microscope with a camera lucida attachment and digital caliper. Regression analysis was used to compare cerebral cortex growth rates by age between the two groups. RESULTS: Cerebral hemisphere width and cerebral index regression line slopes had similar y intercepts (23 day postconception) with significantly (p < .05) diverging slopes over time. Normal rabbits increased more rapidly than synostosed rabbits. No significant (p > .05) differences were noted in regression line slopes between groups for cerebral hemisphere length by age or length by width. CONCLUSIONS: Cerebral dysmorphologies are probably a compensatory, secondary (postsynostotic) event and not a primary causal factor of craniosynostosis in this rabbit model of human familial, nonsyndromic coronal suture synostosis.

Aging↗
PubMed1998

Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway.

Growth factor-dependent survival of a variety of mammalian cells is dependent on the activation of phosphatidylinositol (PI) 3-kinase and its downstream effector, the protein kinase Akt. Glycogen synthase kinase-3 (GSK-3) has been previously identified as a physiological target of Akt, which is inhibited by phosphorylation, so we have investigated the role of GSK-3 in cell survival. Overexpression of catalytically active GSK-3 induced apoptosis of both Rat-1 and PC12 cells, whereas dominant-negative GSK-3 prevented apoptosis following inhibition of PI 3-kinase. GSK-3 thus plays a critical role in regulation of apoptosis and represents a key downstream target of the PI 3-kinase/Akt survival signaling pathway.

Animals↗
PubMed1998

Intact Ras function is required for sustained activation and nuclear translocation of extracellular signal-regulated kinases in nerve growth factor-stimulated PC12 cells.

PC12 pheochromocytoma cell lines expressing the dominant negative Ha-Ras Asn-17 protein at different levels were used in this study to analyze the relationship between nerve growth factor (NGF)-induced activation of members of the mitogen-activated protein kinase (MAPK) family, and neuritogenesis. In wild-type PC12 cells, NGF rapidly stimulated the extracellular signal-regulated kinases (ERKs). Kinase activation was sustained and was followed by the translocation of ERK 1 and ERK 2 into the nucleus ultimately leading to neurite outgrowth. In cells expressing relatively high levels of the inhibitory Ras protein, NGF stimulation of ERK 1 and ERK 2 as well as nuclear translocation of these protein kinases were greatly inhibited. In contrast, in PC12 subclones expressing low amounts of Ha-Ras Asn-17 the peak of ERK activation was only slightly reduced, but became transient in nature and was not followed by nuclear translocation of ERKs 1 and 2. Since all PC12 subclones expressing detectable levels of the dominant inhibitory Ras protein are resistant to NGF induction of neurite formation, our observations support the notion that sustained activation and translocation of ERKs into the nucleus are essential for NGF-induced neuronal differentiation of PC12 cells.

Animals↗
PubMed1998

The influence of intrathecal fentanyl on the characteristics of subarachnoid block for caesarean section.

Forty healthy parturients scheduled for elective Caesarean section were randomly allocated to receive either 0.3 ml 0.9% saline (control group, n = 20), or 15 micrograms (0.3 ml) fentanyl (treatment group, n = 20) added to 2.5 ml 0.5% hyperbaric bupivacaine given intrathecally in the sitting position. A sensory block to T4 was achieved after 6.5 min in those who received fentanyl compared to 8.0 min in the control group; this was not significantly different. The highest level of sensory block achieved in both groups was similar. Ephedrine was required earlier (p < 0.05) in those who received fentanyl but the total requirement of ephedrine intra-operatively was similar. Fentanyl significantly improved the quality of intra-operative surgical anaesthesia as none of the patients in the treatment group complained of discomfort compared with seven in the control group (p < 0.05). Similarly those in the treatment group had better comfort scores as evaluated by visual analogue score (p < 0.01). Regression of anaesthesia to T12 took longer (184 vs 156 min, p < 0.05) in those who received fentanyl but this did not affect the total requirement of morphine in the first 24 h after operation. There was no difference in the incidence of side effects in the mother and no adverse effects were detected in the baby. The results indicate that adding 15 micrograms fentanyl to hyperbaric bupivacaine for spinal anaesthesia markedly improves intra-operative anaesthesia for Caesarean section.

Adult↗
PubMed1998

Intracranial volume in craniosynostotic rabbits.

Although craniosynostosis alters brain growth direction resulting in compensatory changes in the neurocranium, it has been suggested that such compensations occur with little reduction in intracranial volume (ICV). This hypothesis was tested in a rabbit model with nonsyndromic, familial coronal suture synostosis. Cross-sectional three-dimensional computed tomographic head scans were obtained from 79 rabbits (25 normal, 28 with delayed-onset synostosis, and 26 with early-onset synostosis) at 25, 42, and 126 days of age. Intracranial contents were reconstructed and indirect ICV was calculated. Results revealed that by 25 days of age the intracranial contents from early-onset synostosed rabbit skulls showed rostral (anterior) constrictions and a "beaten copper" morphology in the parietal and temporal regions compared with the other two groups. These deformities increased in severity with age. Quantitatively, ICV was significantly reduced (P < 0.05) by 7% in rabbits with early-onset synostosis compared with both control rabbits and rabbits with delayed-onset synostosis at 25 days of age. By 126 days of age, ICV in rabbits with synostosis was significantly reduced (p < 0.05) by 11% in early-onset synostosis and by 8% in delayed-onset synostosis compared with normal rabbits. Results suggest that in rabbits with uncorrected craniosynostosis, compensatory changes in the neurocranium were not adequate to allow normal expansion of the neurocapsular matrix. Further research is needed to determine if ICV reduction is correlated with cerebral atrophy or cerebral spinal fluid (i.e., ventricular or subarachnoid) space compression in this model.

Age of Onset↗
PubMed1998

Internal calvarial bone distraction in rabbits with delayed-onset coronal suture synostosis.

Recent studies have identified a subpopulation of craniosynostotic individuals who exhibit progressive or delayed-onset synostosis and mild craniofacial growth abnormalities. These individuals may be good candidates for nonextirpation, distraction osteogenesis therapy. The present study was designed to test this hypothesis by using internal calvarial bone distraction in a rabbit model with familial delayed-onset craniosynostosis. Data were collected from 159 rabbits: 71 normal controls, 72 with delayed-onset coronal suture synostosis, 8 with delayed-onset coronal suture synostosis and coronal suturectomy, and 8 with delayed-onset coronal suture synostosis and distraction. At 10 days of age, all rabbits had amalgam markers placed on both sides of the frontonasal, coronal, and anterior lambdoidal sutures. At 25 days of age, correction was accomplished through either a 5-mm-wide suturectomy or distraction osteogenesis. An internal distraction appliance was fixed to the frontal and parietal bones and percutaneously and intermittently activated at an average of 0.10 mm/day for 42 days (4.11 mm total). Serial radiographs were taken at 10, 25, 42, and 84 days of age. Results revealed that rabbits with delayed-onset synostosis had significantly (p < 0.01) reduced coronal suture growth rates (0.04 mm/day) compared with the other three groups (0.07 mm/day). Rabbits with suturectomy and rabbits with distraction showed similar coronal suture responses. However, from 42 to 84 days of age, rabbits with distraction showed reduced growth at the vault sutures and abnormal growth patterns in cranial vault width, cranial vault shape, and cranial base angulation compared with the other three groups. Results demonstrated that, although the normal coronal suture growth rate was maintained in rabbits with delayed-onset synostosis using intermittent distraction osteogenesis, normal adult craniofacial structure was not achieved. Such anomalous growth was probably a result of altered growth vectors and compressive forces at adjacent sutures during distraction. These findings suggest that distraction osteogenesis without corticotomy may be a treatment alternative in individuals with progressive, delayed-onset synostosis, but that internal appliances that generate low-level, continuous distractive forces should be investigated and developed.

Animals↗
PubMed1997

Identification of the MDM2 oncoprotein as a substrate for CPP32-like apoptotic proteases.

Programmed cell death is mediated by members of the interleukin 1-beta convertase family of proteases, which are activated in response to diverse cell death stimuli. However, the key substrates of these proteases that are responsible for apoptotic cell death have not been identified. Here we report that the MDM2 oncoprotein is cleaved by members of the CPP32 subfamily of interleukin 1-beta convertase proteases both in vitro and in vivo, resulting in the disappearance of MDM2 from apoptotic cells. Because MDM2 functions as a negative regulator of the p53 tumor suppressor and because p53 induces apoptosis in response to a variety of stimuli, this cleavage of MDM2 by CPP32-like proteases may result in deregulation of p53 and contribute directly to the process of apoptotic cell death.

Amino Acid Sequence↗
PubMed1997

p53-dependent induction of apoptosis by proteasome inhibitors.

Proteolysis by the ubiquitin/proteasome pathway controls the intracellular levels of a number of proteins that regulate cell proliferation and cell cycle progression. To determine whether this pathway of protein turnover was also linked to apoptosis, we treated Rat-1 and PC12 cells with specific proteasome inhibitors. The peptide aldehydes PSI and MG115, which specifically inhibit the chymotrypsin-like activity of the proteasome, induced apoptosis of both cell types. In contrast, apoptosis was not induced by inhibitors of lysosomal proteases or by an alcohol analog of PSI. The tumor suppressor p53 rapidly accumulated in cells treated with proteasome inhibitors, as did the p53-inducible gene products p21 and Mdm-2. In addition, apoptosis induced by proteasome inhibitors was inhibited by expression of dominant-negative p53, whereas overexpression of wild-type p53 was sufficient to induce apoptosis of Rat-1 cells in transient transfection assays. Although other molecules may also be involved, these results suggest that stabilization and accumulation of p53 plays a key role in apoptosis induced by proteasome inhibitors.

Animals↗
PubMed1997

Regulation of neuronal survival by the serine-threonine protein kinase Akt.

A signaling pathway was delineated by which insulin-like growth factor 1 (IGF-1) promotes the survival of cerebellar neurons. IGF-1 activation of phosphoinositide 3-kinase (PI3-K) triggered the activation of two protein kinases, the serine-threonine kinase Akt and the p70 ribosomal protein S6 kinase (p70(S6K)). Experiments with pharmacological inhibitors, as well as expression of wild-type and dominant-inhibitory forms of Akt, demonstrated that Akt but not p70(S6K) mediates PI3-K-dependent survival. These findings suggest that in the developing nervous system, Akt is a critical mediator of growth factor-induced neuronal survival.

Androstadienes↗