Anorexia and pancreatitis associated with a gastric duplication cyst of the pancreas.
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Adolescent↗
Biomedical subjects
J Webster
Publications and source records attributed to J Webster.
Characteristics of sustained blood-brain barrier opening and tissue injury in a model for focal trauma in the rat.
Minor stab wounding of rodent brain by needle or razor blade is a standard model for immunohistochemical investigations of secondary neuronal degeneration and scarring. Opening of the blood-brain barrier (BBB) to plasma molecules and inflammatory cells is integral to the secondary injury process. To facilitate quantitative study of these BBB phenomena, we tested the utility of a stereotaxic wire knife as a minimally invasive way for modeling of focal trauma and bleeding in brain parenchyma and substantial, reproducible BBB damage. Adult rats were anesthetized, and through a skull burr hole, the 0.3-mm dia guide cannula housing a laterally extendable tungsten wire (0.13 mm dia) was inserted into the right striatum. A layering of horizontal disk-like cuts (3 mm dia) was made, producing a cylindrical lesion of approximately 18 mm3 volume, approximately 2.7% of the cerebral hemisphere. Transfer constants (Ki) for blood to brain permeation of [3H]sucrose measured from 30 min to 2 weeks postlesion showed sustained BBB leakiness; for example, mean Ki +/- SEM (nL.g(-1) x s(-1)) for a standard, matrix-dissected forebrain sample enclosing the lesion were 7.2 +/- 1.2 (day 1 postlesion), 8.1 +/-1.4 (day 3), 5.4 +/- 0.8 (day 14) compared with values for contralateral nonlesioned forebrain ranging from 1.3 +/- 0.05 to 1.6 +/- 0.3 (n = 3-4 samples per time point). Analysis of the simultaneous transport of [14C]sucrose (MW = 342 Da) and [3H]inulin (MW approximately 5,000) showed significantly larger upward increments in Ki for sucrose than inulin, indicating a pore-like opening mechanism. Significant edema was measured 3 days postlesion. A reactive glial response was indicated by an increase in S100beta by 6 h and a glial scar forming around the lesion by 7 days. Secondary brain injury was indicated by a 10% loss of hemisphere mass, measured at 2 months. The wire knife enabled tailoring of interstitial trauma with a minimum of extraneous injury and supported reproducible measurements of sustained BBB injury using relatively few animals.
Animals↗
Virus-neutralizing monoclonal antibody expressed in milk of transgenic mice provides full protection against virus-induced encephalitis.
Neutralizing antibodies represent a major host defense mechanism against viral infections. In mammals, passive immunity is provided by neutralizing antibodies passed to the offspring via the placenta or the milk as immunoglobulin G and secreted immunoglobulin A. With the long-term goal of producing virus-resistant livestock, we have generated mice carrying transgenes that encode the light and heavy chains of an antibody that is able to neutralize the neurotropic JHM strain of murine hepatitis virus (MHV-JHM). MHV-JHM causes acute encephalitis and acute and chronic demyelination in susceptible strains of mice and rats. Transgene expression was targeted to the lactating mammary gland by using the ovine beta-lactoglobulin promoter. Milk from these transgenic mice contained up to 0.7 mg of recombinant antibody/ml. In vitro analysis of milk derived from different transgenic lines revealed a linear correlation between antibody expression and virus-neutralizing activity, indicating that the recombinant antibody is the major determinant of MHV-JHM neutralization in murine milk. Offspring of transgenic and control mice were challenged with a lethal dose of MHV-JHM. Litters suckling nontransgenic dams succumbed to fatal encephalitis, whereas litters suckling transgenic dams were fully protected against challenge, irrespective of whether they were transgenic. This demonstrates that a single neutralizing antibody expressed in the milk of transgenic mice is sufficient to completely protect suckling offspring against MHV-JHM-induced encephalitis.
Animals↗
Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.
BACKGROUND: The goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension. METHODS AND RESULTS: Patients who were >/=60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (>/=160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (P<0.001) and, during follow-up, a lower incidence of stroke (P<0.05) and of cardiovascular complications (P=0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (P<0.001). The influence of active treatment on ECG voltages (P<0.05) and on the incidence of stroke (P<0.05) and cardiovascular events (P=0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension. CONCLUSIONS: Patients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.
Aged↗
Multiple copies of beta-lactoglobulin promoter do not function as LCR.
Increasing the number of transcription factor binding sites within a construct can enhance expression. In an attempt to create a synthetic locus control region for mammary expression, we have generated beta-lactoglobulin-reporter constructs with multiple copies of the cluster of transcription sites normally located within the proximal promoter. These constructs were functionally tested by stable transfection of mammary epithelial cells in vitro and in transgenic mice in vivo. Rather than enhancing expression, multimerisation of the promoter region acted neither in vivo nor in vitro to enhance expression. Indeed, its presence reduced expression. This failure to enhance expression was reflected in the inability of this region to form a DNaseI hypersensitive site autonomously in mammary chromatin in vivo. It is implicit from our study that not all combinations of transcription factor binding sites will enhance transcription.
Animals↗
Matrix attachment region regulates basal beta-lactoglobulin transgene expression.
Nuclear matrix attachment regions (MAR) have been implicated in the regulation of gene expression. We have identified a region within the proximal 3'-flanking sequences of the ovine beta-lactoglobulin (betalg) gene that interacts with the nuclear matrix in vitro. No equivalent region was detected in the 5' flanking region. We have investigated the role of this element in regulating betalg expression in vitro and in vivo. Removal of the MAR did not affect the frequency of betalg transgene expression at the mRNA level, but betalg transgenes that lacked the MAR were expressed at a lower level than wild-type betalg transgenes. In neither in-vitro HC11 transfection experiments nor transgenic mice was hormonal induction of betalg expression significantly affected by MAR removal. Nuclear run-on analysis demonstrated that the impaired basal expression of betalg transgene loci lacking the MAR was due to a reduced transcription rate. Thus, the single MAR enhances the basal transcriptional potential of the betalg gene.
Animals↗
The carvedilol hibernation reversible ischaemia trial, marker of success (CHRISTMAS) study. Methodology of a randomised, placebo controlled, multicentre study of carvedilol in hibernation and heart failure.
BACKGROUND: Carvedilol reduces mortality and improves symptoms and ejection fraction in ischemic heart failure, but its mode of action is not well defined and not all patients respond to treatment. The aim of the CHRISTMAS (Carvedilol Hibernation Reversible Ischaemia Trial, Marker of Success) study is to examine whether hibernation may be a significant factor determining this response. This paper describes the methodology and the rationale for the choice of the nuclear cardiology and echocardiography imaging techniques used in the study. METHODS AND RESULTS: The CHRISTMAS study is a double-blind, randomised, parallel group, multinational study of oral carvedilol versus placebo in patients with chronic stable heart failure due to left ventricular systolic dysfunction from coronary artery disease. The study aims to randomise 400 patients who are on optimal treatment. Two parallel groups will be randomised to carvedilol or placebo, namely 200 with hibernating myocardium at baseline and 200 matched patients without. The presence of hibernation is defined from a mismatch between regional contractile function and regional viability, measured by echocardiography (severe segmental asynergy) and nitrate prepared resting Tc99m-MIBI myocardial perfusion imaging (segmental activity >60%). The primary treatment-related end-point of the study is the comparison of the mean change, from baseline to the final visit, in radionuclide-determined left ventricular ejection fraction in patients on placebo with those on carvedilol, between the groups designated as hibernating and non-hibernating. Other end-points being examined include the prevalence of hibernation in heart failure, the relationship between the volume of hibernating myocardium and the ejection fraction response, the prevalence of reversible ischemia in heart failure, and the comparison of echo with gated SPECT. To date, 303 patients have been screened and 251 patients randomised in the study. The study aims to report in 2000. CONCLUSIONS: The CHRISTMAS study addresses the issue of whether the presence of hibernation is a predictor of the ejection fraction response to carvedilol in heart failure. It also examines the potential role of medical therapy in hibernation as well as a number of other end-points. The study may potentially lead to an important new role for nuclear cardiology in heart failure, and demonstrates important synergy between cardiac imaging and the pharmaceutical industry.
Adrenergic beta-Antagonists↗
Spectrophotometric measurement of experimental brain injury.
Freshly sampled brain tissue exposed to 2,3,5-triphenyltetrazolium chloride (TTC) acquires a red color because mitochondrial enzymes reduce the colorless TTC to a red, water-insoluble formazan deposit. Pan-necrotic areas remain uncolored, which enables quantitation of experimental brain injury by optical scanning and image analysis of serial slices to determine the relative volume of red versus infarcted, non-stained, tissue. The accuracy of this method can be challenged, however, when infarction is accompanied by areas of partial, scattered injury where differences in coloration are difficult to see or quantify. We tested the feasibility of measuring scattered injury using a principle which underlies standard assays for in vitro cell survival, namely extracting deposited formazan with a solvent and measuring its level by spectrophotometry. Anesthetized, adult Sprague Dawley rats were subjected to 12 min of cerebral ischemia to produce selective, delayed neuronal death in hippocampus, striatum and cortex. Some rats also received 6 h of whole-body hypothermia treatment (31.5-32.5 degrees C) immediately after ischemia. Ischemia rats and non-operated controls were sacrificed 1 week later. Hippocampus and portions of cerebrum were incubated 90 min in a 2% TTC solution and then soaked in a measured volume of 50:50 ethanol and dimethylsulfoxide to extract the red formazan product. Spectrophotometric measurements of the extract showed a diminished formazan coloration (absorbance/g brain) in all samples from the untreated ischemia group compared to non-operated controls. This apparent brain injury was attenuated in the group of ischemia rats that received hypothermia treatment. We conclude that solvent extraction and spectrophotometric quantitation of formazan has potential utility as an objective way to index experimental brain injury even if this is diffuse in nature and not amenable to measurement by conventional image analysis techniques.
Animals↗
Insulin-like growth factor binding protein-5 (IGFBP-5) potentially regulates programmed cell death and plasminogen activation in the mammary gland.
This study aims to investigate the mechanism by which prolactin and GH interact to maintain mammary epithelial cell function in the rat. IGF-I is an important survival factor for the mammary gland and we have demonstrated that the effects of GH and prolactin involve IGF-I. GH acts by increasing IGF-I whilst prolactin acts by inhibiting the expression of IGFBP-5 from the mammary epithelium. During mammary involution, when serum prolactin levels decline, IGFBP-5 expression is dramatically upregulated and it binds with high affinity to IGF-I preventing IGF-I interaction with the IGF-receptor and thus leading to epithelial cell apoptosis. We have identified a specific interaction of IGFBP-5 with alpha s2-casein. This milk protein has also been shown to bind plasminogen and its activator tissue-type plasminogen activator (tPA) leading to enhanced conversion of plasminogen to plasmin. Plasmin is an important initiator of re-modelling of the extracellular matrix during mammary involution. A potential interaction between the cell death and extracellular matrix remodelling is evident from the observation that IGFBP-5 binds to plasminogen activator inhibitor-I (PAI-1). We thus hypothesized that IGFBP-5 could activate cell death by sequestration of IGF-I and activate plasminogen cleavage by sequestering PAI-1. In support of this hypothesis we have shown that both prolactin and GH inhibit tPA activity and plasminogen activation in the involuting mammary gland. Our results suggest that GH and prolactin inhibit cell death and ECM remodelling via the IGF-axis and also indicate a novel role for the milk protein alpha s2-casein in this process. We have now established lines of transgenic mice expressing IGFBP-5 on the beta-lactoglobulin promoter to explore its function in greater detail.
Animals↗
Development of a district Cord Blood Bank: a model for cord blood banking in the National Health Service.
The Bristol Cord Blood Bank was established as a pilot project within existing health services to establish cost-effective recruitment, collection and processing suitable for use in the NHS should cord blood become a routine source of haemopoietic stem cells for transplantation in the UK. An important aim of the project was to evaluate the feasibility of establishing a midwifery-based collection network, thus utilising expertise already in place. Collection was performed on the delivery suite immediately after the placenta was delivered. The clinical experience of the midwife collector/counsellors allowed rapid pre-collection assessment of the condition of the cord and placenta. This prevented collection attempts from diseased or otherwise damaged placentas, leading to conservation of resources by preventing collection of most small volume donations. The bank was established within the National Blood Service, Bristol Centre to achieve Good Manufacturing Practice standards and ensure that processing was subject to the same stringency required for other sources of haemopoietic stem cells. Cord blood is an expensive resource. By utilising existing expertise in district Obstetric and National Blood Services, the Bristol Cord Blood Bank may serve as a model for health economic evaluation of cord blood banking of volunteer donations within the NHS.
Blood Banks↗
Calcium channel blockers, ACE inhibitors, and the risk of cancer in hypertensive patients: a report from the Department of Health Hypertension Care Computing Project (DHCCP)
OBJECTIVE: Recent studies have shown inconsistent results on the risk of cancer in hypertensive patients using calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors. We investigated a large number of patients from the Department of Health Hypertension Care Computing Project (DHCCP) observational database treated with these drugs for hypertension to see whether the use of CCBs for hypertension is associated with an increased risk of cancer mortality and the use of ACE inhibitors with a reduction. DESIGN: Matched case-control study and a longitudinal study of survival from 1 year after presentation. PATIENTS: A total of 11663 patients treated for hypertension from 1971 through 1987. They were recruited on presentation to one of the hospital hypertension clinics or general practices involved. MAIN OUTCOME MEASURES: Death with any mention of cancer on the death certificate in patients treated with an Index drug group; CCBs, ACE inhibitors, beta adrenergic blocking drugs (BBs), or receiving a diuretic. The treatment groups were mutually exclusive. RESULTS: A total of 391 cases of cancer were matched with 1050 controls. In this case-control study the adjusted relative risk estimate in comparison to diuretic treatment for CCBs was 0.79 (95% CI 0.37 to 1.69), and for CCBs plus a diuretic, 1.05 (0.65 to 1.69). Non-significant results were also observed for ACE inhibitors (1.48 (0.43 to 5.1), and 1.40 (0.56 to 3.50) with a diuretic), and also for the BB and methyldopa groups. In the longitudinal survival study, the adjusted relative risk estimate for CCBs was 1.1 (0.60 to 1.94) and 1.0 (0.53 to 1.86) for CCBs plus a diuretic, and for ACE inhibitors 1.33 (0.37 to 4.76) and 1.47 (0.67 to 3.23), respectively. CONCLUSIONS: In this population there was no increased cancer mortality with the use of CCBs and a relative risk greater than 1.7 to 2.0 was excluded with 95% confidence. The suggestion that ACE inhibitors reduce cancer mortality was not supported with best estimates of relative risk of 1.3 to 1.5 and exclusion of values less than 0.4 to 0.7.
Adolescent↗
Cabergoline and quinagolide therapy for prolactinomas.
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Aminoquinolines↗
Measuring social support in pregnancy: can it be simple and meaningful?
BACKGROUND: It is important to determine the level of a woman's social support at the booking-in interview for prenatal care, but measurement tends to be ad hoc and nonquantifiable. The purpose of this study was to describe the Maternity Social Support Scale and the relationship between support scale ratings and the Edinburgh Postnatal Depression Scale and other health and service use outcomes. METHODS: Women (n = 901) who attended the antenatal clinic at the Royal Women's Hospital in Brisbane, Australia, were asked to complete a support scale as part of their booking-in interview. Participants were contacted at 16 weeks postpartum and invited to complete a follow-up questionnaire. Relationships between the scale and study outcomes were explored using analysis of variance and chi-square tests. RESULTS: Women with low social support in pregnancy were more likely than well-supported women to report poorer health during pregnancy (p = 0.006) and postnatally (p < 0.001), to book later for prenatal care (p = 0.000), to seek medical help more frequently (p = 0.004), and to be more depressed postnatally (p = 0.0001). CONCLUSION: Social support during pregnancy can be measured in a meaningful and simple way through the use of a short questionnaire administered at the prenatal booking-in visit.
Adult↗
Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages.
We examined risk factors for intracranial bleeding while on oral anticoagulants (OACs) in 68 patients admitted to hospital over a 6-year period, and 204 out-patient controls followed-up in an OAC clinic. Under multivariate analysis, significant risk factors for OAC-related intracranial bleeds were hypertension (OR (95%CI) 2.69 (1.04-6.97), duration of OAC therapy < or =12 months (OR 3.74 (1.21-11.56)), duration > or =96 months (OR 0.25 (0.07-0.88)), and International Normalized Ratio on admission >4.5 (OR 10.92 (2.46-48.43)). A logistic regression model including the above variables along with a history of 'cerebrovascular disease' (OR 2.32 (0.98-5.46)) correctly predicted intracranial bleeding (or its absence) during OAC therapy in 85% of all patients. The risk associated with advanced age and concomitant aspirin use was not significantly increased in this analysis. It is important to achieve tight control of INR, particularly in the early months of treatment. Patients with previous cerebrovascular disease are at increased risk of intracranial bleeding on warfarin, and hypertensive patients should have especially close monitoring and optimal control of their blood pressure.
Adolescent↗
Implementation of an oral care standard for leukemia and transplantation patients.
The purpose of this project was to develop an oral care standard on two nursing units in a university hospital where care was given to patients undergoing bone marrow or stem cell transplantation (BMSCT) and other treatments for leukemia. Strategies used in this interdisciplinary effort included collaboration, consultation, education, and evaluation. In the collaboration phase, a core group of nurses talked with staff about current practices, reviewed literature and published standards, examined protocols from other institutions, decided on goals, and developed the standard. Consultation with a dentist, pharmacist, and physician occurred before completion of the standard. The education phase included in-service sessions for nurses and technicians. The evaluation phase, which occurred in two phases, focused on checking to see if the goals had been met, including tolerability and adherence. The first phase allowed identification of problem areas and subsequent revisions, whereas the second phase evaluated adherence at a later time point. Overall, most of the patients adhered to the standard. Future implications include specific recommendations such as an emphasis on oral care, documentation, and patient and staff education. This project is an example of how nurses addressed the challenge of implementing an acceptable oral care standard to decrease patients' oral complications and distress.
Academic Medical Centers↗
Improving antenatal recognition of women at risk for postnatal depression.
The purpose of this study was to assess the effectiveness of a practical antenatal screen used at the Royal Women's Hospital, Brisbane, to identify women at risk for postnatal depression. It was a prospective, hospital-based, cohort study of 901 women (600 with and 301 without prenatal risk factors for postnatal depression). Depression was measured 16 weeks after the birth using the Edinburgh Postnatal Depression Scale. More of the women with a prenatal risk factor for depression (25.9%) scored above 12 on the Edinburgh Postnatal Depression Scale than those without any risk (10.9%) (p < or = 0.001). Low social support (p < or = 0.001), a personal history of mood disorder (p < or = 0.001) and a past history of postnatal depression ( p = 0.002) were all strongly associated with postnatal depression in this sample. Results indicate that an objective, psychosocial assessment during pregnancy improves recognition of women at risk for postnatal depression.
Adult↗
Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage.
BACKGROUND AND PURPOSE: Early survival of patients with intracerebral hemorrhage in general is known to be most strongly dependent on the Glasgow Coma Scale score on admission. The aim of this study was to examine the factors determining functional outcome and in-hospital mortality of patients admitted with an intracerebral hemorrhage related to oral anticoagulant (OAC) use. METHODS: Correlation studies and multiple logistic regression analyses were performed on data from a retrospective series of 42 patients admitted with OAC-related intracerebral hemorrhages over a 6-year period to a tertiary care center in the north of Scotland. RESULTS: The functional outcome after an OAC-related intracerebral hemorrhage was dependent on maximum diameter of hematoma on CT scan (R:=-0.72, P:<0. 001) and international normalized ratio (INR) (R:=-0.35, P:=0.024). Hematoma diameter and INR were not themselves strongly correlated (R:=0.31, P:=0.099). In-hospital mortality can be predicted by the Glasgow Coma Scale score alone (R:(2)=0.36, overall predictive accuracy 68%) but more accurately by a logistic regression model including hematoma diameter and CT signs of cerebrovascular disease (R:(2)=0.70, predictive accuracy 83%). CONCLUSIONS: Neither functional outcome nor in-hospital mortality appears to be strongly dependent on INR measured on admission. CT scan, however, provides essential information and allows accurate predictions about the short-term outcome of OAC-related intracerebral hemorrhages.
Aged↗
Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.
The aim of this study has been twofold: 1--to examine the impact of oral anticoagulant (OAC) use on a possible recent rise in the admission rate of intracerebral haemorrhages to Aberdeen Royal Infirmary (ARI), and 2--to estimate the absolute risk of intracranial haemorrhage for outpatients followed up in the OAC Clinic at ARI. The number of patients admitted to ARI with intracerebral bleedings increased by 60% between 1993 and 1998. A corresponding increase in the proportion of patients with concurrent OAC use (4.7% vs 15.7%, p = 0.055) cannot sufficiently explain the increase in the total number of intracerebral haemorrhages. The average annual incidence of intracranial haemorrhages for the OAC Clinic at ARI is found to be acceptably low at 0.33% per year. Further audit of the large number of patients receiving warfarin outwith the supervision of the clinic is urgently required.
Administration, Oral↗