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Pancreatic secretory trypsin inhibitor (PSTI) is a serine protease inhibitor, expressed in gut mucosa, whose function is unclear. We, therefore, examined the effects of PSTI on gut stability and repair. Transgenic mice overexpressing human PSTI within the jejunum (FABPi−1178 to +28hPSTI construct) showed no change in baseline morphology or morphometry but reduced indomethacin-induced injury in overexpressing hPSTI region by 42% (P< 0.01). Systemic recombinant hPSTI did not affect baseline morphology or morphometry but truncated injurious effects in prevention and recovery rat models of dextran-sodium-sulfate-induced colitis. In vitrostudies showed PSTI stimulated cell migration but not proliferation of human colonic carcinoma HT29 or immortalized mouse colonic YAMC cells. PSTI also induced changes in vectorial ion transport (short-circuit current) when added to basolateral but not apical surfaces of polarized monolayers of Colony-29 cells. Restitution and vectorial ion transport effects of PSTI were dependent on the presence of a functioning epidermal growth factor (EGF) receptor because cells with a disrupted (EGFR−/−immortalized cells) or neutralized (EGFR blocking antibodies or tyrosine kinase inhibitor) receptor prevented these effects. PSTI also reduced the cytokine release of lipopolysaccharide-stimulated dendritic cells. We conclude that administration of PSTI may provide a novel method of stabilizing intestinal mucosa against noxious agents and stimulating repair after injury.

Good contrast is seen between normal tissue and regions of tumor in terahertz pulsed imaging of basal cell carcinoma (BCC). To date, the source of contrast at terahertz frequencies is not well understood. In this paper we present results of a spectroscopy study comparing the terahertz properties (absorption coefficient and refractive index) of excised normal human skin and BCC. Both the absorption coefficient and refractive index were higher for skin that contained BCC. The difference was statistically significant over the range 0.2 to 2.0 THz (6.6 cm−1to 66.6 cm−1) for absorption coefficient and 0.25 to 0.90 THz (8.3 cm−1to 30 cm−1) for refractive index. The maximum difference for absorption was at 0.5 THz (16.7 cm−1). These changes are consistent with higher water content. These results account for the contrast seen in terahertz images of BCC and explain why parameters relating to the reflected terahertz pulse provide information about the lateral spread of the tumor. Knowing the properties of the tissue over the terahertz frequency range will enable the use of mathematical models to improve understanding of the terahertz response of normal and diseased tissue.

Background The relative importance of new risk factors for heart disease singly or in combination is uncertain. We assessed relationships between C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and stable heart disease, as well as interaction with established risk factors.Methods A case-control study of 260 cases of stable heart disease from the Irish component of the European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) II cohort and 260 age, sex-matched controls. C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and conventional risk factors were assayed or recorded. Interaction effects between new and conventional factors were assessed using additive and multiplicative models.Results C-reactive protein, homocysteine, cysteine and von Willebrand factor were significantly higher in cases than controls. Comparing the top fifth with the bottom four-fifths showed independent associations between heart disease and C-reactive protein [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.12–2.86; P= 0.01], cysteine (OR 2.00; 95% CI 1.25–3.20; P= 0.004), von Willebrand factor (OR, 3.0; 95% CI 1.9–4.8; P< 0.0001). For homocysteine, the association was independent comparing the top tenth to the bottom nine-tenths (OR 1.95; 95% CI 1.02–3.41; P= 0.04). Activated factor XII was not associated with risk. The association between C-reactive protein and disease was U-shaped and a graded association existed between homocysteine, cysteine, von Willebrand factor and disease. C-reactive protein, homocysteine, cysteine and von Willebrand factor considerably increased risk associated with other factors, particularly smoking.Conclusions Independent associations exist between stable heart disease and C-reactive protein, homocysteine, cysteine and von Willebrand factor. Strong combined effects were observed between these and conventional risk factors, particularly smoking. Smoking cessation may profoundly reduce risk associated with other risk factors. We found no evidence of a relationship between activated factor XII and disease.

An understanding of the finished structure of complex pharmaceutical coating is becoming desirable, because tablet coatings are now one of the preferred routes to control the release of active pharmaceutical ingredients. There are few nondestructive techniques capable of examining the coatings of compressed tablets; for example laser induced breakdown spectroscopy has been used but this is a destructive method. Terahertz pulsed imaging offers a potential technique to examine coatings quickly and nondestructively. In the study reported herein, it was possible to distinguish between two brands of across‐the‐counter ibuprofen tablets. The terahertz maps obtained were compared with obtained photographs of cut‐through sections; there was good agreement. The technique is fast: a waveform can be obtained in <20 ms allowing the technique to be considered as a candidate for on‐line or at‐line analysis in a process analytical environment. The lateral resolution of the technique is limited by diffraction of the terahertz focus to about 150 μm at 3 THz, whereas the axial resolution is limited by the terahertz pulse duration, which is <200 fs, to about 30 μm.

Terahertz (THz) frequency radiation, 0.1 THz to 20 THz, is being investigated for biomedical imaging applications following the introduction of pulsed THz sources that produce picosecond pulses and function at room temperature. Owing to the broadband nature of the radiation, spectral and temporal information is available from radiation that has interacted with a sample; this information is exploited in the development of biomedical imaging tools and sensors. In this work, models to aid interpretation of broadband THz spectra were developed and evaluated. THz radiation lies on the boundary between regions best considered using a deterministic electromagnetic approach and those better analysed using a stochastic approach incorporating quantum mechanical effects, so two computational models to simulate the propagation of THz radiation in an absorbing medium were compared. The first was a thin film analysis and the second a stochastic Monte Carlo model. The Cole–Cole model was used to predict the variation with frequency of the physical properties of the sample and scattering was neglected. The two models were compared with measurements from a highly absorbing water-based phantom. The Monte Carlo model gave a prediction closer to experiment over 0.1 to 3 THz. Knowledge of the frequency-dependent physical properties, including the scattering characteristics, of the absorbing media is necessary. The thin film model is computationally simple to implement but is restricted by the geometry of the sample it can describe. The Monte Carlo framework, despite being initially more complex, provides greater flexibility to investigate more complicated sample geometries.

Although common genetic variants in platelet collagen receptors influence platelet activation and thrombosis, the impact of polymorphisms in collagen genes on cardiovascular disease is unknown. To evaluate this, we genotyped a highly polymorphic intronic tandem repeat of the COL3A1 gene, encoding collagen type III, alpha 1. This revealed 4 common alleles (COL3A1-1, -2, -3, and -4). The 2 populations studied were as follows: (1) a cross-sectional study of 703 acute coronary syndrome (ACS) patients with myocardial infarction (MI) and unstable angina, and (2) a prospective study of 924 Caucasian patients from the OPUS (Orbofiban in Patients with Unstable coronary Syndromes)-TIMI-16 trial of the oral GPIIb/IIIa antagonist orbofiban. In addition, we studied 306 control subjects and 224 patients with stable angina. In the case-control population, COL3A1-4 carriers were protected against ACS (odds ratio [OR] = 0.57, 95% CI = 0.35-0.91, P = .02) and stable angina (OR = 0.35, 95% CI = 0.16-0.74, P = .006). In the OPUS population, allele 4 again appeared protective against composite end points (death, MI, stroke, recurrent ischemia, and urgent rehospitalization) (relative risk [RR] = 0.41, 95% CI = 0.17-1.00). There were significant interactions between COL3A1-1 and -3 variants and treatment. Allele COL3A1-3 was associated with an increased risk of the composite end point (RR = 1.65, 95% CI = 1.07-2.55) in patients randomized to orbofiban, but appeared protective in placebo patients (RR = 0.53, 95% CI = 0.28-0.98). We conclude that variants in the COL3A1 gene, the product of which is a vessel-wall protein and platelet ligand, modulate the risk of coronary artery disease and could also modulate the response to antithrombotic therapy. This is the first reported association between polymorphisms of extracellular matrix components and cardiovascular risk.

Ischemia/reperfusion of mesenteric vessels is a useful model for acute vascular insufficiency and the early stages of multiorgan failure, conditions associated with high morbidity and mortality. Epidermal growth factor (EGF) is a potent mitogen that shows potential for use in intestinal injury. We therefore examined its influence on this model. Male Sprague-Dawley rats received human recombinant EGF (2 mg/kg i.p., n= 14) or saline (n= 16); 25 minutes before arterial clamping of the superior mesenteric artery (ischemic period) for 60 minutes followed by a final 60-minute reperfusion period. Additional rats were not operated on (controls, n= 7) or had sham operation (laparotomy only, n= 10). Ischemia/reperfusion caused macroscopic damage affecting 56%, 51 to 67% (median, interquartile range), of small intestinal length and intraluminal bleeding. Malondialdehyde levels (free radical marker) increased eightfold compared to nonoperated animals (2400, 2200 to 2700 μmol/mg protein versus290, 250 to 350 μmol/mg protein, P< 0.01) and myeloperoxidase levels (marker for inflammatory infiltrate) increased 15-fold (3150, 2670 to 4180 U/g tissue versus240, 190 to 250 U/g tissue, P< 0.01). Pretreatment with EGF reduced macroscopic injury to 11%, 0 to 15%; prevented intraluminal bleeding; and reduced malondialdehyde and myeloperoxidase levels by ∼60% and 90% (all P< 0.01 versusnon-EGF-treated). Mesenteric ischemia/reperfusion also damaged the lungs and kidneys and increased serum tumor necrosis factor-α levels (circulating cytokine activity marker). EGF pretreatment also reduced these changes. These studies provide preliminary evidence that EGF is a novel therapy for the early treatment or prevention of intestinal damage and multiorgan failure resulting from mesenteric hypoperfusion.

This study examined the influence of the PlApolymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the PlApolymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, PlA2carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P= .004). There was a significant interaction between treatment (placebo and orbofiban) and the PlApolymorphism for bleeding (n = 187; P= .05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71;P< .001) in a dose-dependent fashion, it did not increase bleeding events in PlA2carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the PlApolymorphism for the primary end point (P= .10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P= .04) and MI (RR 4.27, 1.82 to 10.03;P< .001) in PlA2carriers compared with noncarriers. In contrast, there was no evidence that PlA2influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the PlApolymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.

AIM: Recent data have shown that superior mesenteric artery (SMA) flow rates are significantly increased in active Crohn's disease, suggesting that SMA flow may be a useful, non-invasive index of disease activity. The aim of this prospective study was to evaluate the use of SMA Doppler sonography as an indicator of Crohn's disease activity and to compare with clinical evaluation and the Crohn's disease activity index (CDAI). MATERIALS AND METHODS: Patients with active Crohn's (n=19), inactive Crohn's (n=17) and control subjects (n=17) were evaluated. Categorization of disease activity was based on a reference standard. CDAI scores were also calculated independently. The SMA flow parameters evaluated were resistive index, pulsatility index, end diastolic velocity, peak systolic velocity, time averaged maximum velocity, cross-sectional area and maximum flow volume. RESULTS: Using a three-group ANOVA for each of peak systolic velocity (PSV) (P=0.01), end-diastolic velocity (EDV) (P=0.04), pulsatility index (PI) (P=0.003), time-averaged maximum velocity (TAMV) (P=0.05), and maximum flow volume (TAMV.CSA) (P=0.01), there was a significant effect of group. Using post-hoc tests, only EDV (P=0.01), TAMV (P=0.02) and TAMV.CSA (P=0.003) were significantly different between active and inactive Crohn's disease, though with considerable overlap of values for EDV and TAMV. The mean CDAI scores were significantly different between patients with active Crohn's (287) and inactive Crohn's (71) (P=0.0001) and correlated well with the reference standard. CONCLUSION: Only three of several parameters previously described as allowing Crohn's disease activity assessment actually did so in our study. However, for two of these parameters (EDV, TAMV), there was overlap between the measurements in the active and inactive groups, thus limiting the ability to discriminate disease activity in practice. The degree of overlap for maximum flow volume (TAMV.CSA) between active and inactive disease was considerably less and this parameter may be more discriminatory of disease activity. On the other hand, we found CDAI scores to be accurate in disease categorization. We agree that there appear to be hyperdynamic changes in active Crohn's disease but suggest that Doppler ultrasound assessment does not reliably assess disease activity in routine clinical practice. Byrne, M. F.et al. (2001). Clinical Radiology56, 973–978.

Multifrequency EIT (MFEIT) data can be used to form dual-frequency images that display the change of complex resistivity with frequency relative to a selected reference frequency. It has only been possible to calculate the complex resistivity at the image frequency from MFEIT images by assuming some a priori information, such as a homogeneous, resistive reference or a resistivity described by a single dispersion Cole model. The purpose of this paper is to introduce an alternative method of image formation, referred to as "phase magnitude imaging", which enables the complex resistivity of tissue to be obtained independently of the tissue model and without the need for a homogeneous reference. It was expected that the major obstacle to practical application of this technique would be instrumentation errors that affect the measurement of phase. To assess these effects, a cucumber cortex was imaged in a saline-filled tank using an HP4284A impedance analyzer. Cole parameters determined from the phase magnitude images differed by up to 300 from results of the simulation. These errors were reduced to less than 15 by using reciprocity data to partially correct for the influence of stray capacitance on the voltage measurement.

The CD4 T-lymphocyte differentiation antigen is an essential component of the cell surface receptor for human immunodeficiency viruses (HIVs) causing AIDS (acquired immune deficiency syndrome) (refs 1–3). Peripheral blood lymphocytes of apes, New World and Old World monkeys express cell surface antigens homologous to CD4 of human T-helper lymphocytes. The cells of several of these species can be infected in short term culture with diverse strains of the type-1 or type-2 human immunodeficiency viruses (HIV-1 and HIV-2). HIV-1 is the prototype AIDS virus, and HIV-2 is the second type of AIDS virus, prevalent in West Africa4. Infection of the primate cells correlates with evolutionary conservation on CD4 of one particular epitope cluster, and is inhibited by treatment of the cells with monoclonal antibodies to this epitope. The capacity of HIV to replicate in simian cells may provide a means for evaluating antiviral drugs and vaccines.

Studies of basal cell carcinoma using terahertz pulsed imaging have revealed a significant difference between regions of tumor and healthy tissue. These differences are manifested in the reflected pulse due to what is thought to be changes in refractive index and absorption. We present measurements of the refractive index and absorption coefficient of excised normal tissue and basal cell carcinoma using terahertz (THz) transmission spectroscopy. We extract Debye parameters from these data and enter them into a finite difference time domain simulation to predict the shape of the waveforms reflected off the normal tissue and basal cell carcinoma and compare them with published in vivo data. Simulating the interaction of terahertz radiation with normal and cancerous tissue is a key step toward understanding the origin of contrast in terahertz images of skin cancer.