Studies of the luminal environment of the gastro-oesophageal junction

The first chapter of my thesis “The Gastro-oesophageal Junction” discusses the histology of the gastro-oesophageal junction and the components integral to the function of the anti-reflux barrier. It also discusses the pathology found at the gastro-oesophageal junction and describes the nitrite chemistry in this region thought to contribute to this pathology. The second chapter “Mechanisms of Gastro-oesophageal Reflux” discusses the mechanisms of gastro-oesophageal reflux. This includes factors that reduce lower oesophageal pressure, the role of the hiatal hernia and the contribution of transient lower oesophageal sphincter relaxations. The relationship between obesity and reflux disease is also discussed. The third chapter “Research into the Nature of the Acid Pocket” details previous research into the nature of the acid pocket, the primary focus of my own studies. The fourth chapter “Severe Reflux Disease is Associated with Enlarged Unbuffered Proximal Gastric Acid Pocket” details my studies comparing the postprandial acid pocket in healthy subjects and patients with severe reflux disease and my attempt to define its position relative to anatomical and manometric landmarks. 12 healthy subjects and 16 patients with severe reflux disease were studied. While fasted, a station pull-through was performed using a combined dual pH and manometry catheter. Position was confirmed by radiological visualisation of endoscopically-placed radio-opaque clips. The pullthrough study was repeated 15 minutes after a standardized fatty meal. Barium meal examination was performed before and following the meal. A region of unbuffered acid (pH≤2) immediately distal to the proximal gastric folds was more frequent in reflux patients (23/32 studies) than in healthy subjects (11/24) (p<0.05). This unbuffered acid pocket was longer in the reflux patients versus healthy subjects (median length 3cm, range 1cm to 15cm vs. 2 cm, range 1cm to 5cm; p<0.05). The acid pocket extended proximally as far as the proximal gastric folds in the patients but stopped a median of 1.1cm distal in healthy subjects (p=0.005). In healthy subjects the acid pocket occupied the distal portion of the sphincter which opened postprandially, whereas in reflux patients it corresponded to the proximal displacement of the gastric folds i.e. hiatus hernia. The fifth chapter “Paradox Of Gastric Cardia – It Becomes More Acidic Following Meals While The Rest Of Stomach Becomes Less Acidic” details stationary pH studies of the cardia in healthy subjects. The proximal cardia region of the stomach has a high incidence of inflammation, metaplasia and neoplasia. It demonstrates less acid buffering following meals than the more distal stomach. I employed novel high definition pHmetry to investigate acidity at the cardia under fasting conditions and in response to a meal. 15 healthy subjects were studied. A custom made 12 electrode pH catheter was clipped at the squamo-columnar junction with 4 electrodes recording proximal to and 8 distal to the squamo-columnar junction. The most distal pH electrode was located at the catheter tip and 9 electrodes in the region of the squamo-columnar junction were 11mm apart. The electrode situated in the cardia 5.5mm distal to the squamo-columnar junction differed from all other intragastric electrodes during fasting in recording minimal acidity (pH39.%) (p<0.05). The cardia also differed from the rest of the stomach showing a marked increase in acidity in response to the meal (from 2.2% fasting to 58.4% at 60- 70min after meal; p<0.05) while the electrodes distal to the cardia all showed a marked decrease in acidity (p<0.05). These changes in acidity at the cardia following the meal caused the gastric acidity to extend 10mm closer to the squamo-columnar junction. The final discussion chapter discusses the results of our studies and my conclusions. Papers concerning the acid pocket since my own work are also discussed. My studies had full approval from the West Ethics Committee and North Glasgow Trust (COREC Reference 04/50709/26)

High dose atorvastatin associated with increased risk of significant hepatotoxicity in comparison to simvastatin in UK GPRD cohort

Background and Aims: Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods: The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results: Moderate to severe hepatotoxicity [bilirubin &gt;60μmol/L, AST or ALT &gt;200U/L or alkaline phosphatase &gt;1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions: The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small

Social networks : the future for health care delivery

With the rapid growth of online social networking for health, health care systems are experiencing an inescapable increase in complexity. This is not necessarily a drawback; self-organising, adaptive networks could become central to future health care delivery. This paper considers whether social networks composed of patients and their social circles can compete with, or complement, professional networks in assembling health-related information of value for improving health and health care. Using the framework of analysis of a two-sided network – patients and providers – with multiple platforms for interaction, we argue that the structure and dynamics of such a network has implications for future health care. Patients are using social networking to access and contribute health information. Among those living with chronic illness and disability and engaging with social networks, there is considerable expertise in assessing, combining and exploiting information. Social networking is providing a new landscape for patients to assemble health information, relatively free from the constraints of traditional health care. However, health information from social networks currently complements traditional sources rather than substituting for them. Networking among health care provider organisations is enabling greater exploitation of health information for health care planning. The platforms of interaction are also changing. Patient-doctor encounters are now more permeable to influence from social networks and professional networks. Diffuse and temporary platforms of interaction enable discourse between patients and professionals, and include platforms controlled by patients. We argue that social networking has the potential to change patterns of health inequalities and access to health care, alter the stability of health care provision and lead to a reformulation of the role of health professionals. Further research is needed to understand how network structure combined with its dynamics will affect the flow of information and potentially the allocation of health care resources

Analysis of Fascin-1 in Relation to Gleason Risk Classification and Nuclear ETS-Related Gene Status of Human Prostate Carcinomas:An Immunohistochemical Study of Clinically Annotated Tumours From the Wales Cancer Bank

Although prostate-specific antigen (PSA) testing can identify early-stage prostate cancers, additional biomarkers are needed for risk stratification. In one study, high levels of the actin-bundling protein, fascin-1, were correlated with lethal-phase, hormone-refractory prostate cancer. Analyses of independent samples are needed to establish the value of fascin-1 as a possible biomarker. We examined fascin-1 by immunohistochemistry in tumour specimens from the Wales Cancer Bank in comparison with nuclear-located ETS-related gene (ERG), an emerging marker for aggressive prostate cancer. Fascin-1 was elevated in focal areas of a minority of tumours, yet fascin-1-positivity did not differentiate tumours of low-, intermediate-, or high-risk Gleason scores and did not correlate with PSA status or biochemical relapse after surgery. Stromal fascin-1 correlated with high Gleason score. Nuclear ERG was upregulated in tumours but not in stroma. The complexities of fascin-1 status indicate that fascin-1 is unlikely to provide a suitable biomarker for prediction of aggressive prostate cancer

Investigation of additive effects in enantioselective copper-catalysed C-H insertion and aromatic addition reactions of α-diazocarbonyl compounds

Significant enhancements in enantioselectivities and reaction efficiencies in asymmetric copper-catalysed C-H insertion and aromatic addition reactions of α-diazocarbonyl compounds in the presence of various group I salts are reported. For the first time in carbenoid chemistry, evidence for the critical role of the metal cation is described

X-Ray and UV Orbital Phase Dependence in LMC X-3

The black-hole binary LMC X-3 is known to be variable on time scales of days to years. We investigate X-ray and ultraviolet variability in the system as a function of the 1.7 day binary phase using a 6.4 day observation with the Rossi X-ray Timing Explorer (RXTE) from December 1998. An abrupt 14% flux decrease, lasting nearly an entire orbit, is followed by a return to previous flux levels. This behavior occurs twice, at nearly the same binary phase, but it is not present in consecutive orbits. When the X-ray flux is at lower intensity, a periodic amplitude modulation of 7% is evident in data folded modulo the orbital period. The higher intensity data show weaker correlation with phase. This is the first report of X-ray variability at the orbital period of LMC X-3. Archival RXTE observations of LMC X--3 during a high flux state in December 1996 show similar phase dependence. An ultraviolet light curve obtained with the High Speed Photometer aboard the Hubble Space Telescope shows orbital modulation consistent with that in the optical, caused by the ellipsoidal variation of the spatially deformed companion. The X-ray spectrum of LMC X-3 can be acceptably represented by a phenomenological disk-black-body plus a power law. Changes in the spectrum of LMC X-3 during our observations are compatible with earlier observations during which variations in the 2-10 keV flux are tracked closely by the disk geometry spectral model parameter.Comment: 11 pages, 7 figures, ApJ in pres

Pluto's extended atmosphere: An escape model and initial observations

We have calculated the rates of production and hydrodynamic outflow of atomic hydrogen resulting from the photodissociation of methane in the upper atmosphere of Pluto. Under the present near-perihelion conditions this yields an extended cloud of H around Pluto which is likely to be the most easily observable signature of Pluto's extended atmosphere, and thereby provide information on the extent, escape rate, and composition of Pluto's upper atmosphere. We have also performed initial observations with the IUE attempting to detect the H Ly [alpha] emission from the extended H cloud, which we use to derive upper limits to the cloud properties as a function of the cloud extent.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30226/1/0000618.pd

A Survey for Circumstellar Disks Around Young Substellar Objects

(Abridged) We have completed the first systematic survey for disks around spectroscopically identified young brown dwarfs and very low mass stars. We have obtained L'-band (3.8 um) imaging for 38 very cool objects in IC 348 and Taurus. Our targets span spectral types from M6 to M9.5 (~100 to ~15 Mjup). Using the objects' measured spectral types and extinctions, we find that most of our sample (77%+/-15%) possess intrinsic IR excesses, indicative of disks. Because the excesses are modest, conventional analyses using only IR colors would have missed most of the sources with excesses. The observed IR excesses are correlated with Halpha emission, consistent with a common accretion disk origin. The excesses can be explained by disk reprocessing of starlight alone; the implied accretion rates are at least an order of magnitude below typical values for classical T Tauri stars. The observed distribution of IR excesses suggests the presence of inner disk holes. The disk frequency appears to be independent of the mass and age. In the same star-forming regions, disks around brown dwarfs are at least as long-lived (~3 Myr) as disks around the T Tauri stars. Altogether, the frequency and properties of young circumstellar disks appear to be similar from the stellar regime down to the substellar and planetary-mass regime. This provides prima facie evidence of a common origin for most stars and brown dwarfs.Comment: ApJ, in press, 28 pages. Minor change to the online, abridged version of the abstract. No change to the actual pape

Hubble Space Telescope Imaging of the Circumstellar Nebulosity of T Tauri

Short-exposure Planetary Camera images of T Tauri have been obtained using broadband filters spanning the wavelength range 0.55-0.80 μm. The optically visible star lies very close to an arc of reflection nebulosity. The arc's northern arm extends approximately 5" from the star, while its southwestern arm appears brighter and extends only 2". The arc shows an approximate symmetry along an axis toward the west-northwest, the direction of Hind's Nebula and the blueshifted molecular outflow. The morphology of the reflected light is similar to models of scattered light within an illuminated, axisymmetric outflow cavity in a circumbinary envelope, viewed ≈ 45° from the outflow axis. However, our model images do not successfully account for the amount of limb brightening that is seen. No optical counterpart to the infrared companion is seen to a limiting magnitude of V = 19.6, which suggests A_V > 7 mag toward this source. There is no evidence for an optical tertiary, to a limiting ΔV = 5.1 mag fainter than the primary, at the position where such an object has been previously reported