P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps.

BACKGROUND: P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants. METHODOLOGY: IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 µg/mL) and verapa- mil (125 µg/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was deter- mined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test. RESULTS: P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a ne- arly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mome- tasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone. CONCLUSIONS: Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.

The fate of the bone graft in cerebrospinal fluid rhinorrhea endoscopic repair for idiopathic intracranial hypertension: a retrospective case series analysis.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) is a common cause of spontaneous cerebrospinal fluid (CSF) leaks necessitating surgical intervention, and grafting of septal, mastoid, or turbinate bone over the defect is increasingly performed to strengthen the repair of the primary defect. However, the postoperative fate of these grafted bone fragments is largely unknown. METHODOLOGY: We performed a retrospective study of patients at the University of Pennsylvania undergoing repair of spontaneous CSF leaks secondary to IIH. Preoperative and postoperative CTs were analyzed to determine the integration status of the transplanted bone. RESULTS: Fourteen patients with IIH and spontaneous CSF leak were analyzed, with a mean postoperative imaging follow-up period of four years. Thirteen patients (93%) had bone present on CT imaging, with 11 of these patients displaying evidence of bone integration. Two patients (14%) had a recurrent CSF leak in the same area, including the patient with absence of bone on imaging follow-up. CONCLUSIONS: Bone grafts frequently incorporate when used for repair of spontaneous CSF leaks associated with IIH. The rate of incorporation is comparable to bone grafts used for other etiologies of CSF leak, despite the increased pressure on the repair site. Any rigid repair of the leak site should likely be accompanied by treatment of the underlying intracranial hypertension to avoid leak recurrence.

A quick and robust method for measurement of signal-to-noise ratio in MRI.

A novel method is proposed for the measurement of signal-to-noise ratio (SNR) for the purpose of quality assurance (QA) in MRI. A boxcar filtering technique is applied which allows estimation of signal and noise from a single image. The method has been used to estimate SNR in a large set of images acquired in a consistent manner using various scanner models, coils and phantoms. Performance is evaluated by comparison with the double-image subtraction technique incorporating temporal instability correction. The limits of agreement between the techniques are comparable to typical variability in daily SNR, and significantly superior to the performance of other single-image methods published to date. Single-image methods are preferable as they halve the image acquisition time of the recommended double-image approach. Major inaccuracies are identified in methods of SNR measurement currently used for QA in MRI.

Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes.

Human atrial transient outward K(+) current (I(TO)) is decreased in a variety of cardiac pathologies, but how I(TO) reduction alters action potentials (APs) and arrhythmia mechanisms is poorly understood, owing to non-selectivity of I(TO) blockers. The aim of this study was to investigate effects of selective I(TO) changes on AP shape and duration (APD), and on afterdepolarisations or abnormal automaticity with ß-adrenergic-stimulation, using the dynamic-clamp technique in atrial cells. Human and rabbit atrial cells were isolated by enzymatic dissociation, and electrical activity recorded by whole-cell-patch clamp (35-37°C). Dynamic-clamp-simulated I(TO) reduction or block slowed AP phase 1 and elevated the plateau, significantly prolonging APD, in both species. In human atrial cells, I(TO) block (100% I(TO) subtraction) increased APD(50) by 31%, APD(90) by 17%, and APD(-61 mV) (reflecting cellular effective refractory period) by 22% (P < 0.05 for each). Interrupting I(TO) block at various time points during repolarisation revealed that the APD(90) increase resulted mainly from plateau-elevation, rather than from phase 1-slowing or any residual I(TO). In rabbit atrial cells, partial I(TO) block (∼40% I(TO) subtraction) reversibly increased the incidence of cellular arrhythmic depolarisations (CADs; afterdepolarisations and/or abnormal automaticity) in the presence of the ß-agonist isoproterenol (0.1 µm; ISO), from 0% to 64% (P < 0.05). ISO-induced CADs were significantly suppressed by dynamic-clamp increase in I(TO) (∼40% I(TO) addition). ISO+I(TO) decrease-induced CADs were abolished by ß(1)-antagonism with atenolol at therapeutic concentration (1 µm). Atrial cell action potential changes from selective I(TO) modulation, shown for the first time using dynamic-clamp, have the potential to influence reentrant and non-reentrant arrhythmia mechanisms, with implications for both the development and treatment of atrial fibrillation.

Preferential control of induced regulatory T cell homeostasis via a Bim/Bcl-2 axis.

Apoptosis has an essential role in controlling T cell homeostasis, especially during the contraction phase of an immune response. However, its contribution to the balance between effector and regulatory populations remains unclear. We found that Rag1(-/-) hosts repopulated with Bim(-/-) conventional CD4(+) T cells (Tconv) resulted in a larger induced regulatory T cell (iTreg) population than mice given wild-type (WT) Tconv. This appears to be due to an increased survival advantage of iTregs compared with activated Tconv in the absence of Bim. Downregulation of Bcl-2 expression and upregulation of Bim expression were more dramatic in WT iTregs than activated Tconv in the absence of IL-2 in vitro. The iTregs generated following Tconv reconstitution of Rag1(-/-) hosts exhibited lower Bcl-2 expression and higher Bim/Bcl-2 ratio than Tconv, which indicates that iTregs were in an apoptosis-prone state in vivo. A significant proportion of the peripheral iTreg pool exhibits low Bcl-2 expression indicating increased sensitivity to apoptosis, which may be a general characteristic of certain Treg subpopulations. In summary, our data suggest that iTregs and Tconv differ in their sensitivity to apoptotic stimuli due to their altered ratio of Bim/Bcl-2 expression. Modulating the apoptosis pathway may provide novel therapeutic approaches to alter the balance between effector T cells and Tregs.

Mechanisms of termination and prevention of atrial fibrillation by drug therapy.

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na(+) channel blockers, ß-adrenoceptor antagonists, action potential prolonging drugs, and Ca(2+) channel blockers; the "upstream therapies", e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as "atrial-selective" multiple ion channel blockers, gap junction-enhancers, and intracellular Ca(2+)-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms.

Patient dose from 3D rotational neurovascular studies.

The use of image-guided interventional radiological techniques is increasing in prevalence and complexity. Imaging system developments have helped improve the information available to interventionalists to plan and guide procedures. Information on doses to patients resulting from alternative imaging techniques or protocols is useful for both the process of justifying particular procedures and in optimizing the resultant exposures. Such information is not always available, especially for new or developing imaging techniques. We have undertaken a study of doses to patients associated with two alternative imaging methods for pre-intervention assessment of intracranial aneurysms. In the first technique the aneurysm is assessed from a series of digital subtraction angiography (DSA) runs taken at different imaging projections. The second technique involved acquiring images from one single image run while the imaging system rotated 180 degrees around the patient's head. In this technique, the aneurysm was then evaluated from a 3D reconstruction of the projection images. Effective doses were calculated using a computer model to simulate the exposure geometry and parameters. The mean dose from the DSA protocol used at our centre was 3.4 mSv and from the 3D rotational angiography (RA) technique was 0.20 mSv.

Two-dimensional Monte Carlo simulations of ionic and nonionic silane self-assembly on hydrophilic surfaces.

Aqueous chemistries have recently been shown to be useful for the deposition of hydrophobic films of nonionic and cationic silanes on hydrophilic substrates for the prevention of stiction in MEMS. The Monte Carlo method is used to simulate in two dimensions the self-assembly of silane films on a hydrophilic surface. We investigate the impact of charged group in cationic silane on the overall structure of the films. We characterize the film structure with spatial pair correlations at each molecular layer of the deposited films. The simulations reveal long-range correlations for the film of cationic silanes. Based on our two-dimensional simulations, we report an average "most probable" structure for the films of nonionic and cationic silanes.

Assessment of distortion in a three-dimensional rotational angiography system.

The purpose of this project was to determine the degree of geometrical distortion in a three-dimensional (3D) image volume generated by a digital fluorography system with rotational image acquisition capabilities. 3D imaging is a valuable adjunct in neuroangiography for visualization and measurement of cerebral aneurysms and for determination of the optimum projection for intervention. To enable spatially accurate 3D reconstruction the system must correct for geometrical distortion in the image intensifier television system as well as for deviations in gantry motion. 3D volumes were reconstructed from 100 X-ray projections acquired over a 180 degrees arc over a period of 8 s. A phantom was constructed to assess geometrical distortion in the three dimensions. The phantom consisted of 1 mm diameter ball bearings embedded in Perspex in a cubic lattice configuration. The ball bearings were placed at 20 mm intervals over a 140 mm cubic volume. Distortion was assessed by taking measurements between points of known separation and using a differential distortion measurement. The maximum error in the 3D location of objects was found to be 1.4 mm, while the differential distortion was found to range from -1.0% to +2.3%. The 3D images were found to have negligible visual distortion, enabling subjective assessments to be made with confidence to aid intervention.

A comparison of the imaging properties of CCD-based devices used for small field digital mammography.

The objective imaging characteristics of three systems that use charge coupled devices (CCD) for small-field digital mammography (SFDM) have been compared in terms of spatial resolution and signal to noise ratio. The results indicate that although they are designed for nominally the same tasks of stereotactic localization and spot imaging these detectors have significantly differing physical imaging properties. Imaging system design parameters such as the phosphor screen type and thickness, screen configuration and method of optically coupling the phosphor to the CCD have significant effects on the imaging performance of the detectors.

The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation.

OBJECTIVE: To investigate changes in human atrial single cell functional electrophysiological properties associated with chronic atrial fibrillation (AF), and the contribution to these of accompanying ion current changes. METHODS: The whole cell patch clamp technique was used to record action potentials, the effective refractory period (ERP) and ion currents, in the absence and presence of drugs, in enzymatically isolated myocytes from 11 patients with chronic (>6 months) AF and 39 patients in sinus rhythm. RESULTS: Stimulation at high rates (up to 600 beats/min) markedly shortened late repolarisation and the ERP in cells from patients in sinus rhythm, and depolarised the maximum diastolic potential (MDP). Chronic AF was associated with a reduction in the ERP at physiological rate (from 203+/-16 to 104+/-15 ms, P<0.05), and marked attenuation in rate effects on the ERP and repolarisation. The abbreviated terminal phase of repolarisation prevented fast rate-induced depolarisation of the MDP in cells from patients with AF. The density of L-type Ca(2+) (I(CaL)) and transient outward K(+) (I(TO)) currents was significantly reduced in cells from patients with AF (by 60-65%), whilst the inward rectifier K(+) current (I(K1)) was increased, and the sustained outward current (I(KSUS)) was unaltered. Superfusion of cells from patients in sinus rhythm with nifedipine (10 micromol/l) moderately shortened repolarisation, but had no effect on the ERP (228+/-12 vs. 225+/-11 ms). 4-Aminopyridine (2 mmol/l) markedly prolonged repolarisation and the ERP (by 35%, P<0.05). However, the combination of these drugs had no effect on late repolarisation or refractoriness. CONCLUSION: Chronic AF in humans is associated with attenuation in adaptation of the atrial single cell ERP and MDP to fast rates, which may not be explained fully by accompanying changes in I(CaL) and I(TO).

A K(ATP) channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias.

Low concentrations of certain K(ATP) channel openers have been reported to exert a moderate inhibitory effect on arrhythmias during post-ischaemic early myocardial reperfusion, but the accompanying effects on the time course of changes in action potentials in intact hearts have not yet been studied. We report that in rat isolated hearts, reperfusion following 10 min of regional no-flow ischaemia was associated with both an acute, marked, but transient, shortening of ventricular repolarisation (by 63%) during reperfusion, and a high incidence (90%) of ventricular tachyarrhythmias. The K(ATP) channel opener Ro 31-6930 [2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide], delivered prior to ischaemia at a relatively low concentration (0.5 microM), significantly reduced the incidence and duration of reperfusion arrhythmias, and prevented the associated acute action potential shortening during reperfusion, each in a glibenclamide (1 microM)-sensitive manner (P<0.05, n=10-15 hearts). This was associated with a moderate and non-arrhythmogenic action potential shortening during ischaemia (a potentially "cardioprotective" effect). However, these data highlight the potential harm these drugs may cause, since a higher concentration of Ro 31-6930 caused marked shortening of action potentials and significant pro-arrhythmia during ischaemia.

A model for prediction of fume formation rate in gas metal arc welding (GMAW), globular and spray modes, DC electrode positive.

Prediction of fume formation rate during metal arc welding and the composition of the fume are of interest to occupational hygienists concerned with risk assessment and to manufacturers of welding consumables. A model for GMAW (DC electrode positive) is described based on the welder determined process parameters (current, wire feed rate and wire composition), on the surface area of molten metal in the arc and on the partial vapour pressures of the component metals of the alloy wire. The model is applicable to globular and spray welding transfer modes but not to dip mode. Metal evaporation from a droplet is evaluated for short time increments and total evaporation obtained by summation over the life of the droplet. The contribution of fume derived from the weld pool and spatter (particles of metal ejected from the arc) is discussed, as are limitations of the model. Calculated droplet temperatures are similar to values determined by other workers. A degree of relationship between predicted and measured fume formation rates is demonstrated but the model does not at this stage provide a reliable predictive tool.

Radiation doses to patients during ERCP.

BACKGROUND: There is a scarcity of data regarding the radiation dose and associated risks to patients during ERCP. Dose area product (DAP) measurements can be used to estimate an effective dose (ED) to patients undergoing ERCP. This measure allows radiation risk associated with such procedures to be quantified. The aim of this study was to evaluate the ED to patients undergoing ERCP. METHODS: A DAP meter was fitted to the x-ray tube before each ERCP. DAP reading (Gy-cm(2)), fluoroscopy time, average screening kVp, number of films, and kVp per film were recorded. Mean ED was estimated by using DAP readings and Monte Carlo computer software to model radiation exposure conditions. RESULTS: Data were recorded on 20 subjects. Average DAP was 13.5 Gy-cm(2) (6.8-23.9) for diagnostic and 66.8 Gy-cm(2) (28.7-108.5) for therapeutic ERCP (p < 0.05). Average fluoroscopy time was 2.3 minutes (1.1-5.3) for diagnostic and 10.5 minutes (5.9-16.6) for therapeutic ERCP (p < 0.05). DAP showed a linear relationship with fluoroscopy time (R(2) = 0.928). Mean number of diagnostic and therapeutic films was 2.8 and 3.7, respectively. Fluoroscopic exposure represented 69% of the DAP for diagnostic ERCP and 90% of the DAP for therapeutic ERCP. Average ED was 3.1 mSv for diagnostic and 12.4 mSv for therapeutic ERCP. CONCLUSIONS: Therapeutic ERCP is associated with significantly higher radiation exposure than diagnostic ERCP. ED in therapeutic ERCP is a result largely of fluoroscopy time as opposed to number of films.

Rate-dependency of action potential duration and refractoriness in isolated myocytes from the rabbit AV node and atrium.

During atrial fibrillation, ventricular rate is determined by atrioventricular nodal (AVN) conduction, which in part is dependent upon the refractoriness of single AVN cells. The aims of this study were to investigate the rate-dependency of the action potential duration (APD) and effective refractory period (ERP) in single myocytes isolated from the AV node and atrium of rabbit hearts, using whole cell patch clamping, and to determine the contribution of the 4-aminopyridine (4-AP)-sensitive current, I(TO1)to these relationships in the two cell types. AVN cells had a more positive maximum diastolic potential (-60+/-1 v-71+/-2 mV), lower V(max)(8+/-2 v 144+/-17 V/s) and higher input resistance [420+/-46 v 65+/-7 MOmega (mean+/-s.eP<0.05 n=9-33)], respectively, than atrial myocytes. Stepwise increases in rate from 75 beats/min caused activation failure and Wenckebach periodicity in AVN cells (at around 400 beats/min), but 1:1 activation in atrial cells (at up to 600 beats/min). Rate reduction from 300 to 75 beats/min shortened the ERP in both cell types (from 155+/-7 to 135+/-11 ms in AVN cells [P<0.05, n=6] and from 130+/-8 to 106+/-7 ms in atrial cells [P<0.05, n=10]). Rate increase from 300 to 480 and 600 beats/min shortened ERP in atrial cells, by 12+/-4% (n=8) and 26+/-7% (n=7), respectively (P<0.05). By contrast, AVN ERP did not shorten at rates >300 beats/min. In atrial cells, rate reduction to 75 beats/min caused marked shortening of APD(50)(from 51+/-6 to 29+/-6 ms, P<0. 05). 4-AP (1 m m) significantly prolonged atrial APD(50)at 75 beats/min (P<0.05, n=7), but not at 300 or 400 beats/min. In AVN cells, in contrast, there was less effect of rate change on APD, and 4-AP did not alter APD(50)at any rate. 4-AP also did not affect APD(90)or ERP in either cell type. In conclusion, a lack of ERP-shortening at high rates in rabbit single AVN cells may contribute to ventricular rate control. I(TO1)contributed to the APD(50)rate relation in atrial, but not AVN cells and did not contribute to the ERP rate relation in either cell type.

Do KATP channels open as a prominent and early feature during ischaemia in the Langendorff-perfused rat heart?

The objective was to investigate whether myocardial adenosine triphosphate-sensitive K+ (KATP) channels open during the first 10 min of regional ischaemia in Langendorff-perfused rat hearts. Changes in monophasic action potentials and arrhythmias were studied during myocardial ischaemia in both the presence and absence of pharmacological KATP modulation. Ligation of the left main coronary artery for 10 min did not shorten the action potential duration (APD). The APD50 and APD80 (15.5 +/- 1.0 and 38.1 +/- 2.3 ms, respectively [mean +/- S.E., n = 15 hearts], immediately prior to ligation) increased transiently during the first 4 min of ligation (by 160 and 79% respectively, P < 0.05), before returning to pre-ligation values, but without a significant below-baseline-shortening. The cardiac electrogram showed no accompanying ventricular tachyarrhythmia (VT). These results raised the possibility that the myocardial KATP channels had not opened during the ligation. The KATP opener Ro 31-6930 (0.5 and 5 microM) shortened the APD50 and APD80 during coronary ligation, to significantly below both their control and pre-occlusion values (P < 0.05), and caused a concentration-dependent increase in both the incidence and duration of VT during the ligation. Ro 31-6930 at 5 microM also shortened APD50 and APD80 even before ligation (by 50 and 62% respectively, P < 0.05), and abolished the normal APD-lengthening seen during ischaemia. The KATP blocker glibenclamide (1 microM) abolished both the APD-shortening and pro-arrhythmic effects of the KATP opener, both before and during coronary ligation, yet when delivered on its own, at the same concentration which abolished the effects of KATP activation, it had no significant effect on the APD changes seen during the coronary ligation alone. These results suggest that, in Langendorff-perfused rat hearts in the absence of drugs, KATP channels do not open during early myocardial ischaemia.

Application of draft European Commission reference levels to a regional CT dose survey.

A survey of CT doses in Northern Ireland in the period between October 1995 and March 1997 was carried out. The survey included all but one of the 10 scanners in use at the time, and, additionally, two others that were replacement machines. The method used was to study standard protocols and calculate doses to the NRPB mathematical phantom, so that a direct comparison could be made with other surveys carried out in a similar fashion elsewhere. The survey addressed the patient radiation dose but not image quality or clinical outcomes. It is estimated that in Northern Ireland the contribution to collective dose to the population from CT is about 40% of that from all medical X-rays. The proposed European Commission reference quantities, weighted CT dose index and dose-length product were computed and their potential use evaluated. A full study of mean values of effective dose per examination revealed the average dose per examination was not significantly different from that found in the 1989 UK survey, although several procedures gave rise to doses that were high enough to be investigated with a view to justification or reduction. One of the scanners was found to give consistently high doses. It is likely that a revision of the mAs values used on this scanner will produce a significant reduction in patient doses without compromising image quality. When compared with the draft EC reference levels, fewer procedures were found to have excessively high dose values. The proposed EC reference levels would therefore be useful for continual monitoring of CT dose status, but do not appear to provide as comprehensive an assessment of patient exposure as that given by consideration of effective doses.

Ionic basis of a differential effect of adenosine on refractoriness in rabbit AV nodal and atrial isolated myocytes.

OBJECTIVES: Firstly, to compare effects of adenosine on membrane potential and refractoriness in AV nodal and atrial cells. Secondly, to assess the contribution of the effects of adenosine on IKAdo and ICaL to its effects on the functional electrophysiological properties in the two cell types. METHODS: The whole cell patch clamp technique was used to record action potentials and ion currents in AV nodal and left atrial myocytes isolated enzymatically from rabbit hearts. RESULTS: Adenosine (10 microM) caused similar hyperpolarisation and shortening of the action potential duration (APD) in both cell types: maximum diastolic potential was hyperpolarised from -59 +/- 3 to -66 +/- 2 and from -70 +/- 2 to -76 +/- 2 mV (mean +/- SEM) and APD90 was shortened by 31 +/- 4 and 30 +/- 7% in AV nodal (n = 14) and atrial cells (n = 8), respectively. Adenosine shortened the effective refractory period (ERP) in atrial cells, from 124 +/- 15 to 98 +/- 14 ms (n = 8). In contrast, ERP in AV nodal cells was not significantly affected (112 +/- 13 vs. 102 +/- 12 ms, n = 14), and post-repolarization refractoriness was prolonged. By contrast, current injection, to induce an equal degree of hyperpolarisation to that produced by adenosine, shortened APD and ERP in both cell types, suggesting an additional action of adenosine in AV nodal cells. Adenosine (10 microM) did not affect peak ICaL in AV nodal cells, but significantly altered the biexponential time course of recovery of ICaL from inactivation. The proportion of recovery in the fast phase (time constant, tau = 102 +/- 10 ms) was reduced from 71 +/- 3 to 55 +/- 5%, with shift to the slow phase (tau = 858 +/- 168 ms), without altering tau in either phase. A similar effect of adenosine was seen in left atrial cells. CONCLUSION: Adenosine caused hyperpolarisation, APD-shortening and slowing of recovery of ICaL from inactivation, in both AV nodal and atrial cells, but prolonged post-repolarisation refractoriness in AV nodal cells only. This differential effect of adenosine on refractoriness in the two cell types could not be explained by effects on IKAdo, but may be due to slowed reactivation of ICaL, which is the predominant inward current in AV nodal but not left atrial cells.

Differential susceptibility of inbred mouse strains to dextran sulfate sodium-induced colitis.

Dextran sulfate sodium (DSS)-induced murine colitis represents an experimental model for human inflammatory bowel disease. The aim of this study was to screen various inbred strains of mice for genetically determined differences in susceptibility to DSS-induced colitis. Mice of strains C3H/HeJ, C3H/HeJBir, C57BL/6J, DBA/2J, NOD/LtJ, NOD/LtSz-Prkdc(scid)/Prkdc(scid), 129/SvPas, NON/LtJ, and NON.NOD-H2g7 were fed 3.5% DSS in drinking water for 5 days and necropsied 16 days later. Ceca and colons were scored for histological lesions based on severity, ulceration, hyperplasia, and area involved. Image analysis was used to quantitate the proportion of cecum ulcerated. Histological examination revealed significant differences among inbred strains for all parameters scored. In both cecum and colon, C3H/HeJ and a recently selected substrain, C3H/HeJBir, were highly DSS susceptible. NOD/LtJ, an autoimmune-prone strain, and NOD/LtSz-Prkdc(scid)/Prkdc(scid), a stock with multiple defects in innate and adoptive immunity, were also highly DSS susceptible. NON/LtJ, a strain closely related to NOD, was quite DSS resistant. The major histocompatibility (MHC) haplotype of NOD mice (H2g7), a major component of the NOD autoimmune susceptibility, was not crucial in determining DSS susceptibility, since NON mice congenic for this MHC haplotype retained resistance. C57BL/6J, 129/SvPas, and DBA/2J mice showed various degrees of susceptibility, depending upon the anatomical site. A greater male susceptibility to DSS-induced colonic but not cecal lesions was observed. In summary, this study demonstrates major differences in genetic susceptibility to DSS-induced colitis among inbred strains of mice. Knowledge of these strain differences in genetic responsiveness to acute inflammatory stress in the large intestine will permit design of genetic crosses to elucidate the genes involved.