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I Chambers

Publications and source records attributed to I Chambers.

At least 19 recordsLinked to original sources
PubMed2005

Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice.

Leukemia inhibitory factor plays a major role in the uterus and in its absence embryos fail to implant. Our knowledge of the targets for LIF and the consequences of its absence is still very incomplete. In this study, we have examined the ultrastructure of the potential implantation site in LIF-null MF1 female mice compared to that of wild type animals. We also compared expression of proteins associated with implantation in luminal epithelium and stroma. Luminal epithelial cells (LE) of null animals failed to develop apical pinopods, had increased glycocalyx, and retained a columnar shape during the peri-implantation period. Stromal cells of LIF-null animals showed no evidence of decidual giant cell formation even by day 6 of pregnancy. A number of proteins normally expressed in decidualizing stroma did not increase in abundance in the LIF-null animals including desmin, tenascin, Cox-2, bone morphogenetic protein (BMP)-2 and -7, and Hoxa-10. In wild type animals, the IL-6 family member Oncostatin M (OSM) was found to be transiently expressed in the luminal epithelium on late day 4 and then in the stroma at the attachment site on days 5-6 of pregnancy, with a similar but not identical pattern to that of Cox-2. In the LIF-null animals, no OSM protein was detected in either LE or stroma adjacent to the embryo, indicating that expression requires uterine LIF in addition to a blastocyst signal. Fucosylated epitopes: the H-type-1 antigen and those recognized by lectins from Ulex europaeus-1 and Tetragonolobus purpureus were enhanced on apical LE on day 4 of pregnancy. H-type-1 antigen remained higher on day 5, and was not reduced even by day 6 in contrast to wild type uterus. These data point to a profound disturbance of normal luminal epithelial and stromal differentiation during early pregnancy in LIF-nulls. On this background, we also obtained less than a Mendelian ratio of null offspring suggesting developmental failure.

Animals↗
PubMed2005

Bispectral index monitoring may not reliably indicate cerebral ischaemia during awake carotid endarterectomy.

BACKGROUND: Intraoperative ischaemia during carotid cross-clamping in patients undergoing carotid endarterectomy (CEA) is a major complication and prompt recognition of insufficient collateral blood supply is crucial. Electroencephalogram (EEG) is believed to be one of the useful forms of monitoring cerebrovascular insufficiency during CEA. The aim of this study was to evaluate the utility of bispectral index (BIS) monitoring, a processed EEG parameter, for the reliable detection of intraoperative cerebral ischaemia during awake CEA. METHODS: We monitored 52 patients continuously with the BIS monitor together with assessment of neurological function (contralateral upper and lower limb strength and the verbal component of the Glasgow Coma Scale for speech) in patients undergoing awake CEA. RESULTS: Overall mean BIS value in all patients was 96 (SD 2.9). In five patients who showed clinical evidence of cortical ischaemia during carotid cross-clamping, there was no change in the original range of BIS values throughout the procedure (96.7 [3.2]). In one patient BIS values decreased to 38 about 5 min after the incision and recovered within the next 10 min. The mean BIS value in the remaining 46 patients who did not develop clinical signs of ischaemia was 95.4 (2.6). Three cases are presented which demonstrate the inability of the BIS monitor to detect cerebral ischaemia. CONCLUSIONS: Lack of correlation of BIS with the signs of cerebral ischaemia during CEA makes it unreliable for detection of cerebrovascular insufficiency. We conclude that awake neurological testing is the preferred method of monitoring in these patients.

Aged↗
PubMed2005

Survey of traumatic brain injury management in European Brain-IT centres year 2001.

BACKGROUND: The aim of this study was to obtain basic knowledge about the current local conditions and neurointensive care of traumatic brain injury (TBI) in the new multi-centre collaborative BrainIT group. MATERIALS AND METHODS: The survey comprised a background part on local policies (Part A), and a case study section (Part B). The information was gathered by questionnaire followed by telephone interviews. Twenty-three BrainIT centres participated in the survey and answers from two respondents were available from 18 of the sites. RESULTS: The average proportion of agreement between duplicate respondents was 0.778 (range 0.415-1.00). All BrainIT centres monitored ICP. The treatment protocols seem to have a pattern concerning escalation of treatment of intracranial hypertension: 1/ evacuation of mass lesions and head elevation; 2/ increased sedation and mannitol; 3/ hyperventilation; 4/ ventricular drainage; 5/ craniectomy and barbituates. CONCLUSIONS: There seemed to be an agreement on neurointensive care policies within the BrainIT group. The suggested order of treatment was generally in accordance with published guidelines although the suggested order and combinations of different treatments varied. Variation of treatment within the range of prescribed standards provides optimal conditions for an interesting future analysis of treatment and monitoring data in reality using the BrainIT database.

Brain Injuries↗
PubMed2005

The BrainIT Group: concept and current status 2004.

INTRODUCTION: An open collaborative international network has been established which aims to improve inter-centre standards for collection of high-resolution, neurointensive care data on patients with traumatic brain injury. The group is also working towards the creation of an open access, detailed and validated database that will be useful for hypothesis generation. In Part A, we describe the underlying concept of the group and it's aims and in Part B we describe the current status of the groups development. METHODS: Four group meetings funded by the EEC have enabled definition of a "Core Dataset" to be collected from all centres regardless of specific project aim. A form based feasibility study was conducted and a prospective data collection exercise of core data using PC and hand held computer based methods is in progress. FINDINGS: A core-dataset was defined and can be downloaded from the BrainIT web-site (go to "Core dataset" link at: www.brainit.org). A form based feasibility study was conducted showing the overall feasibility for collection of the core data elements was high. Software tools for collection of the core dataset have been developed. Currently, 130 patient's data from 16 European centres have been recruited to the joint database as part of an EEC funded proof of concept study. INTERPRETATION: The BrainIT network provides a more standardised and higher resolution data collection mechanism for research groups, organisations and the device industry to conduct multicentre trials of new health care technology in patients with traumatic brain injury.

Brain Injuries↗
PubMed2005

Accurate data collection for head injury monitoring studies: a data validation methodology.

BACKGROUND: BrainIT is a multi centre, European project, to collect high quality continuous data from severely head injured patients using a previously defined [6] core data set. This includes minute-by-minute physiological data and simultaneous treatment and management information. It is crucial that the data is correctly collected and validated. METHODS: Minute-by-minute physiological monitoring data is collected from the bedside monitors. Demographic and clinical information, intensive care management and secondary insult management data, are collected using a handheld computer. Data is transferred from the handheld device to a local computer where it is reviewed and anonymised before being sent electronically, with the physiological data, to the central database in Glasgow. Automated computer tools highlight missing or ambiguous data. A request is then sent to the contributing centre where the data is amended and returned to Glasgow. Of the required data elements 20% are randomly selected for validation against original documentation along with the actual number of specific episodic events during a known period. This will determine accuracy and the percentage of missing data for each record. CONCLUSION: Advances in patient care require an improved evidence base. For accurate, consistent and repeatable data collection, robust mechanisms are required which should enhance the reliability of clinical trials, assessment of management protocols and equipment evaluations.

Brain Injuries↗
PubMed2005

The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells.

Intrinsic regulators of the pluripotency of mouse ES (embryonic stem) cells include the homeodomain proteins Oct4 and the recently identified Nanog. When overexpressed, Nanog displays the unique attribute of robustly sustaining ES cell self-renewal in the absence of the otherwise requisite extracellular stimulation by LIF (leukaemia inhibitory factor) and BMP (bone morphogenetic protein). Here, we review our current understanding of the function of Nanog in pluripotent stem cells both in vitro and in vivo.

Animals↗
PubMed2004

Bench test assessment of the new Raumedic Neurovent-P ICP sensor: a technical report by the BrainIT group.

BACKGROUND: In clinical practice, fiberberoptic and piezo-electric ICP probes are often used for measuring intracranial pressure (ICP). A number of similar technologies, although performing well in bench test studies, have been shown to exhibit unacceptable zero drift, fragility or both during trials conducted under clinical conditions. Recently, a new technology has become available, the Neurovent-P (Raumedic AG + CO, Raumedic, Germany). As a pre-requisite for a clinical trial, we have conducted and report on bench test studies to confirm the manufacturer's long term zero-drift performance for this technology. METHOD: In a test rig static tests (recording of 20 mmHg pressure) and dynamic tests, ranging from 5 to 50 mmHg have been performed. FINDINGS: 10 ICP probes have been tested for a total of 60 days. All the catheters, after the connection with the ICU monitor displayed a static pressure of 0 +/- 1 mmHg and did not required pre-insertion alteration. At five days, mean zero drift was 0.6 +/- 0.9 mmHg. Overall, zero drift ranged from 0 to 2 mmHg. At a fixed static pressure of 20 mmHg, the mean recorded value was 20.6 +/- 0.8 mmHg, ranging from 19 to 23 mmHg. A regression analysis of the relationship between the applied pressure and the recorded pressure during the dynamic tests of the 10 catheters yielded a correlation coefficient R2 of 0.997. Applying the Altman and Bland method to assess the bias and confidence limits for the Raumedic catheter responses during the dynamic tests against the applied gold-standard hydrostatic column pressures, the average bias of -0.66 +/- 0.85 mmHg, with 95% CLs of -2 mmHg and 1 mmHg. CONCLUSIONS: Mean zero drift, after five days, was very small and long-term continuous recording of a stable pressure was very precise. The response at dynamic tests, i.e. the changes of pressure in a wide range, was excellent. The average bias of the Raumedic catheter compared with the hydrostatic column is very small. After this bench test, the next and most critical step will be to conduct a trial of this promising technology under more demanding clinical environment.

Calibration↗
PubMed2004

Identification of genes regulated by leukemia-inhibitory factor in the mouse uterus at the time of implantation.

The endometrium is prepared for implantation by the actions of estradiol (E2) and progesterone (P4). In mice the luminal epithelium (LE) only becomes fully receptive to the attaching blastocyst in response to the nidatory estrogen surge on d 4 of pregnancy. The cytokine leukemia-inhibitory factor (LIF) is rapidly induced by nidatory estrogen and has been shown to be the primary mediator of its action. Implantation fails in the absence of LIF, and injection of LIF on d 4 of pregnancy can substitute for the nidatory estrogen. In this study, we sought to identify genes regulated by LIF in the uterine epithelium. We used oligonucleotide microarrays to compare the transcript profiles of paired uterine horns from LIF-deficient MF1 mice after intraluminal injection of LIF or PBS on d 4 of pseudopregnancy. IGF-binding protein 3 was identified as a gene up-regulated by LIF; this was confirmed by RT-PCR. In situ hybridization showed that the primary site of IGF-binding protein 3 expression is the luminal epithelium (LE), the known site of LIF action in the uterus. We identified two other genes: amphiregulin and immune response gene-1, the expression of which were also up-regulated by LIF. Immune response gene 1 has recently been shown to be essential for implantation. Expression of all three of these genes in the LE is known to be regulated by P4. The expression of osteoblast-specific factor 2 and leukocyte 12/15 lipoxygenase, which are also expressed in LE under the control of P4, were not increased by LIF. This suggests that one of the actions of LIF on LE may be to enhance the expression of a subset of P4-regulated genes.

Amphiregulin↗
PubMed2004

R3-survey of traumatic brain injury management in European Brain IT centres year 2001.

OBJECTIVE: To obtain knowledge about the conditions and management of traumatic brain injury (TBI) in a collaborative network of Brain Information Technology centres. DESIGN: The Brain IT (Brain monitoring with Information Technology) survey comprised two parts: local conditions and policies (part A), and a case study part (part B). The information was gathered by written questionnaires followed by telephone interviews. PARTICIPANTS: Twenty-four Brain IT centres participated (two respondents from 18 sites). RESULTS: The average proportion of agreement between duplicate respondents was 0.79 (range 0.44-1.00). All Brain IT centres monitored ICP. The reported order of treatment for intracranial hypertension was: evacuation of mass-lesions and head elevation (1), increase of sedation and Mannitol scheme (2), hyperventilation (3), ventricular drainage (4), craniectomy and pentothal coma (5), and decompressive lobectomy (6). The respondents were less prone to evacuate expansive contusions in relation to extra cerebral hematomas. The most common suggested interventions (alone or in combination) for treatment of intracranial hypertension without mass lesions was the Mannitol scheme (included in 71% of the suggestions), CSF drainage (included in 56%), hyperventilation (included in 32%), and pentothal coma (included in 22%). CONCLUSIONS: The suggested management of TBI was mainly in accordance with published guidelines, although a minor proportion of the answers deviated to some extent. The suggested order and combinations of different treatment interventions varied. Variation of treatment within the range of prescribed standards provides optimal conditions for an interesting future analysis of treatment and monitoring data as collected prospectively in a Brain IT database.

Adult↗
PubMed2003

The BrainIT group: concept and core dataset definition.

INTRODUCTION: An open collaborative international network has been established which aims to improve inter-centre standards for collection of high-resolution, neurointensive care data on patients with traumatic brain injury. The group is also working towards the creation of an open access, detailed and validated database that will be useful for post-hoc hypothesis testing. In Part A, the underlying concept, the group coordination structure, membership guidelines and database access and publication criteria are described. Secondly, in part B, we describe a set of meetings funded by the EEC that allowed us to define a "Core Dataset" and we present the results of a feasibility exercise for collection of this core dataset. METHODS: Four group meetings funded by the EEC have enabled definition of a "Core Dataset" to be collected from all centres regardless of specific project aim. A paper based pilot collection of data was conducted to determine the feasibility for collection of the core dataset. Specially designed forms to collect the core dataset demographic and clinical information as well as sample the time-series data elements were distributed by both email and standard mail to 22 BrainIT centres. A deadline of two months was set to receive completed forms back from centres. A pilot data collection of minute by minute physiological monitoring data was also performed. FINDINGS: A core-dataset was defined and can be downloaded from the BrainIT web-site (go to "Core dataset" link at: www.brainit.org). Eighteen centres (82%) returned completed forms by the set deadline. Overall the feasibility for collection of the core data elements was high with only 10 of the 64 questions (16%) showing missing data. Of those 10 fields with missing data, the average number of centres not responding was 12% and the median 6%. An SQL database to hold the data has been designed and is being tested. Software tools for collection of the core dataset have been developed. Ethics approval has been granted for collection of multi-centre data as part of a pilot data collection study. INTERPRETATION: The BrainIT network provides a more standardised and higher resolution data collection mechanism for research groups, organisations and the device industry to conduct multi-centre trials of new health care technology in patients with traumatic brain injury.

Brain Injuries↗
PubMed2001

Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines.

Embryonic stem cells are established directly from the pluripotent epiblast of the preimplantation mouse embryo. Their derivation and propagation are dependent upon cytokine-stimulated activation of gp130 signal transduction. Embryonic stem cells maintain a close resemblance to epiblast in developmental potency and gene expression profile. The presumption of equivalence between embryonic stem cells and epiblast is challenged, however, by the finding that early embryogenesis can proceed in the absence of gp130. To explore this issue further, we have examined the capacity of gp130 mutant embryos to accommodate perturbation of normal developmental progression. Mouse embryos arrest at the late blastocyst stage when implantation is prevented. This process of diapause occurs naturally in lactating females or can be induced experimentally by removal of the ovaries. We report that gp130(-/-) embryos survive unimplanted in the uterus after ovariectomy but, in contrast to wild-type or heterozygous embryos, are subsequently unable to resume development. Inner cell masses explanted from gp130(-/-) delayed blastocysts produce only parietal endoderm, a derivative of the hypoblast. Intact mutant embryos show an absence of epiblast cells, and Hoechst staining and TUNEL analysis reveal a preceding increased incidence of cell death. These findings establish that gp130 signalling is essential for the prolonged maintenance of epiblast in vivo, which is commonly required of mouse embryos in the wild. We propose that the responsiveness of embryonic stem cells to gp130 signalling has its origin in this adaptive physiological function.

Animals↗
PubMed2000

Continuous monitoring of ICP and CPP following ICH and its relationship to clinical, radiological and surgical parameters.

Sixty-two patients with a spontaneous supratentorial haemorrhage had continuous Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) monitoring. In addition to the recordings of physiological data their past medical history, presenting neurological state, Computed Tomograph (CT) findings, daily Glasgow Coma Score (GCS) and outcome were noted. The mean age was 57.6 years (sd 13.3). Onset of recording, after ictus was at a mean of 32.6 hours (sd 26.0). Average length of recording was 62.0 hours (sd 39.8). Thirty-one patients had evacuation of haematoma, 6 insertion of External Ventricular Drain (EVD). Preoperative measures of ICP were significantly related to delayed neurological deterioration, death within three days and Glasgow Outcome Scale (GOS) at neurosurgical discharge. No such relationships existed with preoperative measures of CPP and neither ICP nor CPP was related to outcome at 6 months. Post-operative measures of both ICP and CPP demonstrated a significant relationship with death within three days of ictus and GOS at neurosurgical discharge. Again no relationship existed with these parameters and outcome at six months. Surgical evacuation of haematoma acted to significantly reduce ICP and improve CPP. Given that these factors seem to be related to deterioration, death and early outcome, it would seem that surgery could play a role in reducing mortality and improving outcome following Intra cerebral Haemorrhage (ICH).

Blood Pressure↗
PubMed1999

Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells.

The propagation of pluripotent mouse embryonic stem (ES) cells depends on signals transduced through the cytokine receptor subunit gp130. Signalling molecules activated downstream of gp130 in ES cells include STAT3, the protein tyrosine phosphatase SHP-2, and the mitogen-activated protein kinases, ERK1 and ERK2. A chimaeric receptor in which tyrosine 118 in the gp130 cytoplasmic domain was mutated did not engage SHP-2 and failed to activate ERKs. However, this receptor did support ES cell self-renewal. In fact, stem cell colonies formed at 100-fold lower concentrations of cytokine than the unmodified receptor. Moreover, altered ES cell morphology and growth were observed at high cytokine concentrations. These indications of deregulated signalling in the absence of tyrosine 118 were substantiated by sustained activation of STAT3. Confirmation that ERK activation is not required for self-renewal was obtained by propagation of pluripotent ES cells in the presence of the MEK inhibitor PD098059. In fact, the growth of undifferentiated ES cells was enhanced by culture in PD098059. Thus activation of ERKs appears actively to impair self-renewal. These data imply that the self-renewal signal from gp130 is a finely tuned balance of positive and negative effectors.

Animals↗
PubMed1999

Signaling mechanisms regulating self-renewal and differentiation of pluripotent embryonic stem cells.

An ability to propagate pluripotent embryonic cells in culture is the foundation both for defined germline modification in experimental rodents and for future possibilities for broad-based cellular transplantation therapies in humans. Yet, the molecular basis of the self-renewing pluripotent phenotype remains ill-defined. The relationship between factors that influence embryonic stem cell propagation in vitro and mechanisms of stem cell regulation operative in the embryo is also uncertain. In this article we discuss the role of intracellular signalling pathways in the maintenance of pluripotency and induction of differentiation in embryonic stem cell cultures and the mammalian embryo.

Animals↗
PubMed1998

Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway.

The propagation of pluripotential mouse embryonic stem (ES) cells is sustained by leukemia inhibitory factor (LIF) or related cytokines that act through a common receptor complex comprising the LIF receptor subunit (LIF-R) and the signal transducer gp130. However, the findings that embryos lacking LIF-R or gp130 can develop beyond gastrulation argue for the existence of an alternative pathway(s) governing the maintenance of pluripotency in vivo. In order to define those factors that contribute to self-renewal in ES cell cultures, we have generated ES cells in which both copies of the lif gene are deleted. These cells showed a significantly reduced capacity for regeneration of stem cell colonies when induced to differentiate, confirming that LIF is the major endogenous regulatory cytokine in ES cell cultures. However, self-renewal was not abolished and undifferentiated ES cell colonies were still obtained in the complete absence of LIF. A differentiated, LIF-deficient, parietal endoderm-like cell line was derived and shown to support ES cell propagation via production of a soluble, macromolecular, trypsin-sensitive activity. This activity, which we name ES cell renewal factor (ESRF), is distinct from members of the IL-6/LIF family because (i) it is effective on ES cells lacking LIF-R; (ii) it is not blocked by anti-gp130 neutralizing antibodies; and (iii) it acts without activation of STAT3. ES cells propagated clonally using ESRF alone can contribute fully to chimaeras and engender germline transmission. These findings establish that ES cell pluripotency can be sustained via a LIF-R/gp130-independent, STAT-3 independent, signaling pathway. Operation of this pathway in vivo could play an important role in the regulation of pluripotency in the epiblast and account for the viability of lifr -/- and gp130 -/- embryos.

Animals↗
PubMed1998

Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.

Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.

Animals↗