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Biomedical subjects

R Young

Publications and source records attributed to R Young.

At least 19 recordsLinked to original sources
PubMed2006

Can the laboratory affect the investigation and diagnosis of primary biliary cirrhosis?

BACKGROUND: Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterised by the presence of various laboratory abnormalities but the precise role of laboratory staff in initiating clinical referral and subsequent biopsy is not clear. OBJECTIVE: To examine the impact of laboratory abnormalities in the investigation of PBC. METHODS: In a retrospective study of laboratory results over nine years from 1996, computer records were reviewed to identify how many referrals for biopsy were initiated and subsequent diagnoses made as a result of clinical signs, raised serum alkaline phosphatase activity (ALP), raised IgM concentration, or positive mitochondrial antibodies accompanied by a clinical comment from the laboratory suggesting further action. RESULTS: 22 diagnoses of PBC were confirmed by histopathology. Eleven had high ALP activity which had follow up tests initiated by the laboratory (mitochondrial antibodies or IgM or both) and a comment added suggesting further investigation into the possibility of PBC. Seven had abnormal liver antibodies and one had a high polyclonal IgM concentration which prompted the relevant follow on testing and comments. One had an earlier diagnosis made on serological/clinical grounds and the biopsy was a confirmatory measure. One had no liver related antibodies. One had a request by laboratory staff for follow on tests but these were not asked for in subsequent samples by the requesting clinician. CONCLUSIONS: There is a positive role for laboratory staff in the diagnosis of PBC. Unexplained rises in ALP activity, positive mitochondrial antibodies, or raised IgM concentrations should be investigated more fully by laboratory staff and advice given to prompt a clinical referral for review and biopsy.

Adult↗
PubMed2006

Comparing perfusion metrics obtained from a single compartment versus pharmacokinetic modeling methods using dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade.

BACKGROUND AND PURPOSE: Numerous different parameters measured by perfusion MR imaging can be used for characterizing gliomas. Parameters derived from 3 different analyses were correlated with histopathologically confirmed grade in gliomas to determine which parameters best predict tumor grade. METHODS: Seventy-four patients with gliomas underwent dynamic susceptibility contrast-enhanced MR imaging (DSC MR imaging). Data were analyzed by 3 different algorithms. Analysis 1 estimated relative cerebral blood volume (rCBV) by using a single compartment model. Analysis 2 estimated fractional plasma volume (V(p)) and vascular transfer constant (K(trans)) by using a 2-compartment pharmacokinetic model. Analysis 3 estimated absolute cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) by using a single compartment model and an automated arterial input function. The Mann-Whitney U test was used make pairwise comparisons. Binary logistic regression was used to assess whether rCBV, V(p), K(trans), CBV, CBF, and MTT can discriminate high- from low-grade tumors. RESULTS: rCBV was the best discriminator of tumor grade ype, followed by CBF, CBV, and K(trans). Spearman rank correlation factors were the following: rCBV = 0.812 (P < .0001), CBF = 0.677 (P < .0001), CBV = 0.604 (P < .0001), K(trans) = 0.457 (P < .0001), V(p) = 0.301 (P =.009), and MTT = 0.089 (P = .448). rCBV was the best single predictor, and K(trans) with rCBV was the best set of predictors of high-grade glioma. CONCLUSION: rCBV, CBF, CBV K(trans), and V(p) measurements correlated well with histopathologic grade. rCBV was the best predictor of glioma grade, and the combination of rCBV with K(trans) was the best set of metrics to predict glioma grade.

Adolescent↗
PubMed2004

MR-trackable intramyocardial injection catheter.

There is growing interest in delivering cellular agents to infarcted myocardium to prevent postinfarction left ventricular remodeling. MRI can be effectively used to differentiate infarcted from healthy myocardium. MR-guided delivery of cellular agents/therapeutics is appealing because the therapeutics can be precisely targeted to the desired location within the infarct. In this study, a steerable intramyocardial injection catheter that can be actively tracked under MRI was developed and tested. The components of the catheter were arranged to form a loopless RF antenna receiver coil that enabled active tracking. Feasibility studies were performed in canine and porcine myocardial infarction models. Myocardial delayed-enhancement (MDE) imaging identified the infarcted myocardium, and real-time MRI was used to guide left ventricular catheterization from a carotid artery approach. The distal 35 cm of the catheter was seen under MRI with a bright signal at the distal tip of the catheter. The catheter was steered into position, the distal tip was apposed against the infarct, the needle was advanced, and a bolus of MR contrast agent and tissue marker dye was injected intramyocardially, as confirmed by imaging and postmortem histology. A pilot study involving intramyocardial delivery of magnetically labeled stem cells demonstrated the utility of the active injection catheter system.

Animals↗
PubMed2004

Pressures within air-filled tracheal cuffs at altitude--an in vivo study.

Aeromedical transport of mechanically ventilated critically ill patients is now a frequent occurrence. However, the performance of the air filled tracheal tube cuff at altitude has not been studied in vivo. We measured the tracheal cuff pressures at ground level and at 3000 ft, in 10 intubated patients. With air providing the seal in the cuff the mean rise in cuff pressure was 23 cmH2O, which took the pressures above the critical perfusion pressure of the tracheal mucosa. This could lead to tracheal injury.

Aerospace Medicine↗
PubMed2004

Diagnosis and management of thyroid disease and the critically ill patient.

OBJECTIVE: To review current concepts in the diagnosis and management of thyroid disease in the critically ill patient. DATA SOURCES: A review of articles reported on thyroid disease and the acutely ill patient. SUMMARY OF REVIEW: Normal thyroid function depends on an integrated response between the pituitary and thyroid gland to provide an appropriate circulating T4 level which is converted to T3 by peripheral tissues. Thyroid hormone increases oxygen consumption and regulates lipid and carbohydrate metabolism and normal growth and maturation of tissues. In patients with a severe non-thyroidal illness, the thyroid stimulating hormone (TSH), free thyroxine (FT4) and free 3,5,3-triiodo-L-thyronine (FT3) levels decrease. Dopamine, dobutamine or corticosteroid therapy may also reduce TSH levels. The TSH and T4 levels often return to low normal levels, although with continued severe illness they may remain low. The clinically euthyroid state is maintained in the presence of a reduction in FT3 levels partly due to an increase in synthesis of tissues T3 receptors. During the recovery phase of the illness, there is often a transient elevation in the TSH level until the FT4 and FT3 levels are returned to normal. There are no clinical data that have shown a consistent reduction in mortality with thyroid hormone treatment in the critically ill patient. In general, in the absence of clinical signs of thyroid disease, abnormal thyroid function tests should not be treated in the critically ill patient and thyroid function studies should be repeated after the acute illness has resolved. Hypothyroid and hyperthyroid states may present with acute cardiorespiratory failure. Treatment that includes cardiorespiratory resuscitation and thyroid hormone replacement in hypothyroid states and beta adrenergic blockers in hyperthyroid states will often allow correction of the underlying disorder to be achieved successfully. CONCLUSIONS: Abnormal thyroid function tests are commonly found in the critically ill patient and do not require treatment. However, hypothyroid and hyperthyroid states may present with acute cardiorespiratory failure and require careful and specific management strategies to resolve the thyroid disorder.

Journal Article↗
PubMed2004

Current concepts in the management of heart failure.

OBJECTIVE: To review current concepts in the management of patients with heart failure. DATA SOURCES: A review of articles reported on acute and chronic heart failure. SUMMARY OF REVIEW: Heart failure has been defined as that state which occurs when the heart fails to maintain the needs of the body despite a satisfactory venous return. While it has been divided functionally into high-output failure and low-output failure, it is often used to describe patients with left ventricular low-output failure and is divided into systolic or diastolic heart failure, depending on left ventricular ejection fraction. The clinical features are due largely to venous congestion and reduction in cardiac output with symptoms of fatigue, orthopnoea, paroxysmal nocturnal dyspnoea and peripheral oedema being common complaints. Plasma natriuretic peptide levels are elevated in patients with symptomless left ventricular failure and have been useful in diagnosing heart failure in patients admitted with acute dyspnea. Treatment of heart failure is aimed at correcting both the underlying disorder as well as the precipitating cause (e.g. ischaemia, valvular heart disease, anaemia, thyrotoxicosis, etc), as well as reducing cardiac work, enhancing myocardial contractility and treating the complications (e.g. reducing salt and water retention, and neurohumoral activation). Angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, beta-blockers and spironolactone have all been associated with a reduction in mortality in patients with chronic heart failure. While digoxin and diuretics are used to reduce the number of episodes of pulmonary oedema, they have not been associated with a significant reduction in mortality. Surgery (e.g. transplantation, mechanical assist devices) has a definite place in young patients with chronic dilated cardiomyopathy with severe heart failure although other therapeutic agents (e.g. growth hormone, thyroxine and antioxidants) are yet to be shown to be of benefit. CONCLUSIONS: Heart failure is a common condition caused by many disorders leading to left ventricular dysfunction. Management of the underlying disorder (e.g. ischaemia, valvular disease, hypertension) maintenance of sinus rhythm, as well as reducing excessive neurohumoral activation (ACE inhibitors, angiotensin receptor antagonists, beta-blockers, spironolactone) can reduce mortality and improve morbidity in patients with chronic heart failure.

Journal Article↗
PubMed2003

Prognostic indicators for gastrointestinal stromal tumours: a clinicopathological and immunohistochemical study of 108 resected cases of the stomach.

AIMS: Whether immunohistochemical markers increase accuracy in predicting prognosis for gastrointestinal stromal tumours (GISTs) remains uncertain. However, past studies have used only small, heterogeneous patient groups. Our aim was to test previously studied and more novel morphological features as well as four immunohistochemical markers as prognostic indicators amongst a large cohort of surgically resected, gastric GISTs. METHODS AND RESULTS: Tissues from 127 gastric mesenchymal tumours were collected retrospectively and subjected to repeat histological assessment and immunophenotyping. Further immunohistochemistry was performed for Ki67, p53, Bcl-2 and cyclin D1. Complete follow-up data were collected for 108 patients with immunophenotyped diagnoses of GIST (i.e. c-kit+ tumours). At the census point, 52 patients were alive, 24 had died from their GISTs and the remainder of other causes. Univariate analysis showed the following predicted for shorter disease-specific survival: size > or =50 mm; necrosis, no intratumoral lymphocytes; mitotic count > or =5/50 high power fields; Ki67 labelling index > or =5%; p53 immunopositivity. Of these variables, multivariate analyses showed only mitotic count and, to a lesser extent, Ki67 labelling to be independent prognostic indicators. CONCLUSIONS: Mitotic count remains the best predictor of outcome following surgical resection of gastric GISTs. Ki67 immunohistochemistry does not provide better prognostication and p53, Bcl-2 and cyclin D1 immunohistochemistry provide no additional prognostication.

Adult↗
PubMed2003

Seasonal pseudohyperkalaemia.

AIMS: To investigate the relation between ambient temperature and serum potassium concentrations in samples from primary care. METHODS: Potassium concentrations were estimated on general practitioner and hospital ward samples taken over a two year period using serum obtained from gel separator samples. The number of samples analysed from general practice during each month varied from 5093 to 8978 (mean of 7068 samples/month). RESULTS: As the temperature fell in winter, the mean daily serum potassium concentration rose in samples from general practice, with the inverse occurring during the warmer summer months. This effect was restricted to samples coming from general practice, with inpatient samples seemingly unaffected. CONCLUSIONS: These results indicate that exposure of the samples to variations in ambient temperature during their transport to the laboratory profoundly affects measured serum potassium concentrations.

Blood Preservation↗
PubMed2003

A comparative analysis: storm water pollution policy in California, USA and Victoria, Australia.

Urban drainage systems historically were developed on principles of hydraulic capacity for the transport of storm water to reduce the risk of flooding. However, with urbanization the percent of impervious surfaces increases dramatically resulting in increased flood volumes, peak discharge rates, velocities and duration, and a significant increase in pollutant loads. Storm water and urban runoff are the leading causes of the impairment of receiving waters and their beneficial uses in Australia and the United States today. Strict environmental and technology controls on wastewater treatment facilities and industry for more than three decades have ensured that these sources are less significant today as the cause of impairment of receiving waters. This paper compares the approach undertaken by the Environmental Protection Authority Victoria for the Melbourne metropolitan area with the approach implemented by the California Environmental Protection Agency for the Los Angeles area to control storm water pollution. Both these communities are largely similar in population size and the extent of urbanization. The authors present an analysis of the different approaches contrasting Australia with the USA, comment on their comparative success, and discuss the relevance of the two experiences for developed and developing nations in the context of environmental policy making to control storm water and urban runoff pollution.

California↗
PubMed2002

Adult mesenchymal stem cells: potential for muscle and tendon regeneration and use in gene therapy.

The expansion potential and plasticity of stem cells, adult or embryonic, offer great promise for their use in medical therapies. Recent provocative data suggest that the differentiation potential of adult stem cells may extend to lineages beyond those usually associated with the germ layer of origin. In this review, we describe recent developments related to adult stem cell research and in particular, in the arena of mesenchymal stem cell (MSC) research. Research demonstrates that transduced MSCs injected into skeletal muscle can persist and express secreted gene products. The ability of the MSC to differentiate into cardiomyocytes has been reported and their ability to engraft and modify the pathology in infarcted animal models is of great interest. Research using MSCs in tendon repair provides information on the effects of physical forces on phenotype and gene expression. In turn, MSCs produce changes in their matrix environment in response to those biomechanical forces. Recent data support the potential of MSCs to repair tendon, ligament, meniscus and other connective tissues. Therapeutic applications of adult stem cells are approaching clinical use in several fields, furthering the possibility to regenerate damaged and diseased tissue.

Journal Article↗
PubMed2001

Calmodulin-binding and autoinhibitory domains of Acanthamoeba myosin I heavy chain kinase, a p21-activated kinase (PAK).

The sequence homology between Acanthamoeba myosin I heavy chain kinase (MIHCK) and other p21-activated kinases (PAKs) is relatively low, including only the catalytic domain and a short PAK N-terminal motif (PAN), and even these regions are not highly homologous. In this paper, we report the expression in insect cells of full-length, fully regulated Acanthamoeba MIHCK and further characterize the regulation of this PAK by Rac, calmodulin, and autoinhibition. We map the autoinhibitory region of MIHCK to its PAN region and show that the PAN region inhibits autophosphorylation and kinase activity of unphosphorylated full-length MIHCK and its expressed catalytic domain but has very little effect on either when they are phosphorylated. These properties are similar to those reported for mammalian PAK1. Unlike PAK1, MIHCK is activated by Rac only in the presence of phospholipid. However, peptides containing the PAN region of MIHCK bind Rac in the absence of lipid, and Rac binding reverses the inhibition of the MIHCK catalytic domain by PAN peptides. Our data suggest that a region N-terminal to PAN is required for optimal binding of Rac. Also unlike mammalian PAK, phospholipid stimulation of Acanthamoeba MIHCK and Dictyostelium MIHCK) (which is also a PAK) is inhibited by Ca(2+)-calmodulin. In contrast to Dictyostelium MIHCK, however, Ca(2+)-calmodulin also inhibits Rac-induced activity of Acanthamoeba MIHCK. The basic region N-terminal to PAN is essential for calmodulin binding.

Acanthamoeba↗
PubMed2001

Holins kill without warning.

Holins comprise the most diverse functional group of proteins known. They are small bacteriophage-encoded proteins that accumulate during the period of late-protein synthesis after infection and cause lysis of the host cell at a precise genetically programmed time. It is unknown how holins achieve temporal precision, but a conserved feature of their function is that energy poisons subvert the normal scheduling mechanism and instantly trigger membrane disruption. On this basis, timing has been proposed to involve a progressive decrease in the energized state of the membrane until a critical triggering level is reached. Here, we report that membrane integrity is not compromised after the induction of holin synthesis until seconds before lysis. The proton motive force was monitored by the rotation of individual cells tethered by a single flagellum. The results suggest an alternative explanation for the lysis "clock," in which holin concentrations build to a critical level that leads to formation of an oligomeric complex that disrupts the membrane.

Bacteriophages↗
PubMed2001

Physiological and regulatory roles of activin A in late pregnancy.

Unexplained fetal death in utero in late pregnancy represents an increasing proportion of perinatal deaths. It has been assumed that critical hypoxia is the likely mechanism underlying these losses, but the lack of a physiological marker has hampered both confirmation and prediction which could lead to timely intervention. In this paper, we report studies on hypoxia that we have performed in chronically cannulated late pregnant sheep, complemented by parallel investigations undertaken in human pregnancies. Our initial studies were directed towards determining activin secretion in the fetus and mother during late gestation, and immediately after fetal surgery using a sheep model. This led us to propose that there may be a relationship between hypoxia and activin A, follistatin and prostaglandin (PG) release from the feto-placental unit. Subsequent studies have been directed towards examining this potential relationship in sheep and in humans with compromised pregnancies. As a result of these studies, we have identified a potential mechanism by which activin A may be involved in regulating the response of the fetus to hypoxic insult. Activin A and follistatin concentrations increased in late gestation in ovine maternal plasma and in fetal fluids. Feto-placental hypoxemia or maternal isocapnic hypoxemia, leading to fetal hypoxia, were specific triggers for an acute increase in fetal activin A and follistatin concentrations during late gestation. The source and secretion of activin A, follistatin, and the associated release of PGE(2,) from within the feto-placental unit varied according to the site of the insult. The concomitant secretion of activin A and PGE(2) into the fetal circulation and amniotic fluid during reduced uterine blood flow provides an insight into the physiological regulatory mechanisms that might be involved. Changes observed in maternal activin A concentrations in mid and late gestation in the human may also be associated with fetal compromise. In human pregnancies, elevated activin A concentrations were observed in maternal plasma in mid and late gestation, in association with severe pre-eclampsia and with severe fetal growth restriction, compared to those observed in pregnancies with constitutionally small, healthy fetuses. Activin A was also elevated in maternal and arterial cord plasma in women at term during labour and immediately prior to undergoing emergency Caesarean section for failure to progress. These findings offer exciting new possibilities to gain insights into the mechanisms that underlie the maintenance of fetal wellbeing and provide a rationale for the potential that activin A may prove to be a useful clinical marker of fetal distress.

Activins↗
PubMed2001

A protein antibiotic in the phage Qbeta virion: diversity in lysis targets.

A(2), a capsid protein of RNA phage Qbeta, is also responsible for host lysis. A(2) blocked synthesis of murein precursors in vivo by inhibiting MurA, the catalyst of the committed step of murein biosynthesis. An A(2)-resistance mutation mapped to an exposed surface near the substrate-binding cleft of MurA. Moreover, purified Qbeta virions inhibited wild-type MurA, but not the mutant MurA, in vitro. Thus, the two small phages characterized for their lysis strategy, Qbeta and the small DNA phage phiX174, effect host lysis by targeting different enzymes in the multistep, universally conserved pathway of cell wall biosynthesis.

Alkyl and Aryl Transferases↗
PubMed2001

Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial.

CONTEXT: Severe gastroesophageal reflux disease (GERD) is a lifelong problem that can be complicated by peptic esophageal stricture and adenocarcinoma of the esophagus. OBJECTIVE: To determine the long-term outcome of medical and surgical therapies for GERD. DESIGN AND SETTING: Follow-up study conducted from October 1997 through October 1999 of a prospective randomized trial of medical and surgical antireflux treatments in patients with complicated GERD. Mean (median) duration of follow-up was 10.6 years (7.3 years) for medical patients and 9.1 years (6.3 years) for surgical patients. PARTICIPANTS: Two hundred thirty-nine (97%) of the original 247 study patients were found (79 were confirmed dead). Among the 160 survivors (157 men and 3 women; mean [SD] age, 67 [12] years), 129 (91 in the medical treatment group and 38 in the surgical treatment group) participated in the follow-up. MAIN OUTCOME MEASURES: Use of antireflux medication, Gastroesophageal Reflux Disease Activity Index (GRACI) scores, grade of esophagitis, frequency of treatment of esophageal stricture, frequency of subsequent antireflux operations, 36-item Short Form health survey (SF-36) scores, satisfaction with antireflux therapy, survival, and incidence of esophageal adenocarcinoma, compared between the medical antireflux therapy group and the fundoplication surgery group. Information on cause of death was obtained from autopsy results, hospital records, and death certificates. RESULTS: Eighty-three (92%) of 90 medical patients and 23 (62%) of 37 surgical patients reported that they used antireflux medications regularly (P<.001). During a 1-week period after discontinuation of medication, mean (SD) GRACI symptom scores were significantly lower in the surgical treatment group (82.6 [17.5] vs 96.7 [21.4] in the medical treatment group; P =.003). However, no significant differences between the groups were found in grade of esophagitis, frequency of treatment of esophageal stricture and subsequent antireflux operations, SF-36 standardized physical and mental component scale scores, and overall satisfaction with antireflux therapy. Survival during a period of 140 months was decreased significantly in the surgical vs the medical treatment group (relative risk of death in the medical group, 1.57; 95% confidence interval, 1.01-2.46; P =.047), largely because of excess deaths from heart disease. Patients with Barrett esophagus at baseline developed esophageal adenocarcinomas at an annual rate of 0.4%, whereas these cancers developed in patients without Barrett esophagus at an annual rate of only 0.07%. There was no significant difference between groups in incidence of esophageal cancer. CONCLUSION: This study suggests that antireflux surgery should not be advised with the expectation that patients with GERD will no longer need to take antisecretory medications or that the procedure will prevent esophageal cancer among those with GERD and Barrett esophagus.

Adenocarcinoma↗
PubMed2001

Genetic analysis of the T4 holin: timing and topology.

The t protein of bacteriophage T4 shares with other holins the ability to cause the formation of a lethal membrane lesion which allows the phage endolysin to attack the peptidoglycan. Moreover, T, like other holins, acts in a saltatory manner at a precisely programmed time in the vegetative cycle. Unlike other holins, however, T has the unique ability to postpone its lethal function in response to a secondary infection by a T-even phage during the vegetative cycle. A signal transduction system that responds to the secondary infection is thought to be encoded by some of the numerous r genes, defined by mutations that abolish this lysis-inhibition (LIN) response. The primary structure of T differs from two main structural patterns found in more than 30 orthologous groups of holins. Genetic approaches were taken to probe the t sequence for features involved in membrane localization, functional timing and LIN regulation. Gene fusion analysis indicates that T has a single TMD near the N-terminus, with the bulk of the protein residing in the periplasm. Mapping and phenotypic analysis of deletion and point mutations in t indicates that the periplasmic domain of T is the major determinant of the timing mechanism and is involved in the LIN response.

Alkaline Phosphatase↗