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Biomedical subjects

R Mukherjee

Publications and source records attributed to R Mukherjee.

At least 91 records · Page 5Linked to original sources

The epidemiology of cancer of the small bowel.

Despite its anatomical location between two regions of high cancer risk, the small bowel rarely develops a malignant tumor. However, in recent years, small bowel cancer incidence rates have begun to rise. The purpose of this review is to explore the descriptive and analytic epidemiology of small bowel cancer for those factors that protect this organ and those factors associated with loss of this protection. Within the small intestine, the sites at the highest risk are the duodenum, for adenocarcinomas, and the ileum, for carcinoids and lymphomas. In industrialized countries, small bowel cancers are predominantly adenocarcinomas; in developing countries, lymphomas are much more common. The incidence of small bowel cancer rises with age and has generally been higher among males than among females. The risk factors for small bowel cancer include dietary factors similar to those implicated in large bowel cancer, cigarette smoking, alcohol intake, and other medical conditions, including Crohn's disease, familial adenomatous polyposis, cholecystectomy, peptic ulcer disease, and cystic fibrosis. The protective factors may include rapid cell turnover, a general absence of bacteria, an alkaline environment, and low levels of activating enzymes of precarcinogens. Adenocarcinomas of the small and large bowel are similar in risk factors and geographic distribution but not in recent time trends; colorectal cancer incidence rates in the United States have been falling since the mid-1980s. Small bowel lymphoma may be associated with infectious agents, such as HIV. Given the differences in anatomic and geographic location among histological subtypes, much may be learned from well-designed, histology-specific epidemiological and genetic studies of cancer of the small bowel.

Adenocarcinoma↗

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: I. Effects on left ventricular performance and neurohormonal systems.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition (ACEI) alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade on LV function, systemic hemodynamics, and neurohormonal system activity in a model of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) AT1 Ang II receptor blockade (valsartan, 3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (4) ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). In the pacing group, LV fractional shortening (LVFS) fell (13.4+/-1.4% versus 39.1+/-1.0%) and end-diastolic dimension (LVEDD) increased (5.61+/-0.11 versus 3.45+/-0.07 cm) compared with control (P<.05). With AT1 Ang II blockade and rapid pacing, LVEDD and LVFS were unchanged from pacing-only values. ACEI reduced LVEDD (4.95+/-0.11 cm) and increased LVFS (20.9+/-1.9%) from pacing-only values (P<.05). ACEI and AT1 Ang II blockade reduced LVEDD (4.68+/-0.07 cm) and increased LVFS (25.2+/-0.9%) from pacing only (P<.05). Plasma norepinephrine and endothelin increased by more than fivefold with chronic pacing and remained elevated with AT1 Ang II blockade. Plasma norepinephrine was reduced from pacing-only values by more than twofold in the ACEI group and the combination group. ACEI and AT1 Ang II receptor blockade reduced plasma endothelin levels by >50% from rapid-pacing values. CONCLUSIONS: These findings suggest that the effects of ACEI in the setting of CHF are not solely due to modulation of Ang II levels but rather to alternative enzymatic pathways and that combined ACEI and AT1 Ang II receptor blockade may provide unique benefits for LV pump function and neurohormonal systems in the setting of CHF.

Aldosterone↗

Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes.

BACKGROUND: The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process. METHODS AND RESULTS: Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group. CONCLUSIONS: The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.

Analysis of Variance↗

Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Beneficial effects on left ventricular and myocyte function.

BACKGROUND: Plasma levels of endothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present project tested the hypothesis that chronic blockade of the ETA receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF. METHODS AND RESULTS: Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400 bpm, 3 weeks), RVP and concomitant administration of the selective ETA receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17 +/- 5 versus 42 +/- 3%) and end-diastolic dimension increased (2.36 +/- 0.44 versus 1.24 +/- 0.18 cm) compared with controls (P < .05). With RVP plus ETA blockade, LV fractional shortening was increased (33 +/- 6%) and end-diastolic dimension decreased (2.02 +/- 0.30 cm) compared with RVP-only values (P < .05). Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ETA blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42 +/- 13 versus 72 +/- 10 microns/s, P < .05) compared with controls but was normalized with RVP plus ETA blockade (77 +/- 16 microns/s). Myocyte inotropic response to extracellular Ca2+, beta-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ETA receptor blockade. CONCLUSIONS: The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ETA receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ETA receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.

Animals↗

Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists.

Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.

Animals↗

Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists.

We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPARgamma2 and hPPARgamma1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPARgamma activators. Human PPARgamma binds to DNA as a heterodimer with the retinoid X receptor (RXR). This heterodimer was activated by both RXR agonists and antagonists and the addition of PPARgamma ligands with retinoids resulted in greater than additive activation. Such heterodimer-selective modulators may have a role in the treatment of PPARgamma/RXR-modulated diseases like diabetes. Northern blot analysis indicated the presence of PPARgamma in skeletal muscle, and a sensitive RNase protection assay confirmed the presence of only PPARgamma1 in muscle that was not solely due to fat contamination. However, both PPARgamma1 and PPARgamma2 RNA were detected in fat, and the ratio of PPARgamma1 to PPARgamma2 RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPARgamma1 to PPARgamma2 raised the possibility that isoform expression may be modulated in disease states like non-insulin-dependent diabetes mellitus. Interestingly, a third protected band was detected with fat RNA indicating the possible existence of a third human PPARgamma isoform.

Amino Acid Sequence↗

Effects of chronic angiotensin-converting enzyme inhibition on left ventricular and myocyte structure and function during recovery from chronic rapid pacing.

LV and myocyte function and angiotensin converting enzyme (ACE) activity with ACE inhibitor (ACEI) treatment were examined in four groups of dogs (n = 6 each): (1) control; (2) with 4 weeks of recovery from chronic rapid pacing (REC: 216 beats/min), (3) ACEI for the first 14 days of REC (ACEI--14), and (4) ACEI for 28 days of REC (ACEI--28). Three additional control dogs were administered ACEI for 28 days. LV mass increased with REC compared to control (146 +/- 6 v 92 +/- 3 g, P < 0.05), was unaffected with ACEI--14, and was decreased with ACEI--28 compared to REC (111 +/- 8 g, P < 0.05). Myocyte function was decreased in REC compared to controls (43 +/- 3 v 63 +/- 3 microns/s, P < 0.05) and was similarly reduced with ACEI--14. However, with ACEI--28, myocyte shortening velocity was increased compared to REC (56 +/- 1 microns/s, P < 0.05). Myocyte beta-adrenergic response was decreased with REC and ACEI--14 compared to controls (53 +/- 9 and 57 +/- 14, respectively v 127 +/- 14 microns/s, P < 0.05). ACEI--28 resulted in a normalization of myocyte beta-adrenergic responsiveness (108 +/- 3 microns/s). LV myocardial ACE activity increased in REC compared to control (5.82 +/- 0.21 v 3.51 +/- 0.15 nmol/mg/min, P < 0.05). With ACEI--14 or ACEI--28, myocardial ACE activity was decreased compared to REC (4.16 +/- 0.06 and 4.08 +/- 0.23 nmol/mg/min; P < 0.05). In control dogs administered ACEI, there were no differences in any of these parameters compared to controls. The unique findings in this study were: (1) effects of ACEI treatment in this model of LV hypertrophy were time dependent with respect to LV mass and LV and myocyte function; and (2) the effect of ACEI treatment on the degree of LV hypertrophy appears to not be solely due modulation of myocardial ACE activity.

Adrenergic beta-Agonists↗

Left ventricular regional myocyte contractility in normal and heart failure states.

Fundamental determinants of left ventricular (LV) pump performance are preload, afterload and myocyte contractility. Regional variability in LV end systolic wall stress, an important index of LV afterload, has been well defined in both control and congestive heart failure (CHF) states. The goal of this study was to examine end systolic wall stress and myocyte contractile function in three circumferential regions of the LV in both control and CHF states. Accordingly, LV end systolic wall stress and myocyte velocity of shortening were measured from the basal, mid and apical regions in control pigs (n=5) and following the induction of pacing-induced CHF (3 weeks, 240 beats/min, n=5). LV mid wall, circumferential, end systolic wall stress decreased from base to apex in both control (35+/-7 v 16+/-4 g/cm2, P<0.05) and CHF (155+/-23 v 92+/-24 g/cm2, P<0.05) states. In the CHF group, LV end systolic wall stress was elevated by 300% compared to control values in all regions. LV myocyte velocity of shortening was equivalent in the basal and mid regions of control myocytes (52+/-2 v 57+/-2 m/s), and was higher in the apical region (63+/-3 microm/s, P<0.05). In the CHF group, LV myocyte velocity of shortening was reduced by 45% compared to controls with no regional variation. beta-adrenergic stimulation increased myocyte velocity in both the control and CHF groups, however, regional variation was observed only in the CHF group. These unique results demonstrated that minimal regional variations in myocyte contractile function exist in both control and congestive heart failure states, and does not necessarily parallel patterns of regional LV end systolic wall stress.

Animals↗

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist.

INTRODUCTION: Blockade of the AT1 angiotensin II (Ang II) receptor has been shown to provide anti-hypertensive effects. However, whether AT1 Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear. METHODS AND RESULTS: Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n = 13) and guinea pig (n = 9) myocardial preparations in the presence of the specific AT1 Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mumol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mumol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mumol/L of valsartan, resting membrane potential increased from baseline in both rat (-82.3 +/- 4.1 vs -76.8 +/- 5.8 mV, p < 0.05) and guinea pig (-81.6 +/- 2.9 vs -76.9 +/- 2.0 mV, p < 0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7 +/- 1.4 vs 80.0 +/- 5.6 ms, p < 0.05) and ventricular (131.1 +/- 8.1 vs 118.7 +/- 8.3 ms, p < 0.05) myocardium following exposure to 500 mumol/L of valsartan. In a separate series of experiments, Ang II (1.0 mumol/L) had no effect on atrial or ventricular action potential characteristics in either species. CONCLUSION: Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.

Angiotensin Receptor Antagonists↗

The relation between changes in myocyte orientation and contractile function with electrical field stimulation.

The cardiac myocyte is the fundamental contractile unit of the heart, and therefore recent studies have examined myocyte function through electrical field stimulation. However, the relation between changes in electrical field orientation and myocyte contractile function remains unclear. Accordingly, the goal of the present study was to measure myocyte contractile function with known changes in myocyte orientation with respect to the electrodes. Isolated left ventricular porcine myocytes (n = 32) were field stimulated (0.5 - 1.5 Hz, 5 ms, double contraction threshold) in a thermostatically controlled chamber. Myocyte velocity of shortening was measured by high speed video microscopy. Myocyte position was altered and quantified with respect to the electrodes. When myocyte position approached alignment with the electrodes, contractile activity ceased. Contractile activity resumed when the myocyte moved greater than 25 degrees from the parallel position. When contractions could be successfully elicited, the velocity of shortening was 48+/-15 microm/s and did not differ at any orientation. These results suggest that angular orientation should be carefully considered when evaluating the contractile performance of electrically stimulated myocytes.

Animals↗

Protective effects of adenosine on myocyte contractility during cardioplegic arrest.

BACKGROUND: Adenosine delivery to the left ventricular myocardium has been demonstrated to provide protective effects in the setting of ischemia and reperfusion. However, whether adenosine has direct protective effects on isolated myocytes in the setting of cardioplegic arrest was unclear. METHODS: Isolated porcine left ventricular myocytes were assigned to one of the following treatment groups: (1) cardioplegia: 24 mEq/L K+, 4 degrees C for 2 hours followed by rewarming (cell media, 37 degrees C; n = 29); (2) cardioplegia augmented with adenosine (1 to 200 micromol/L) followed by rewarming (n = 98); and (3) normothermic control (cell media, 37 degrees C, 2 hours; n = 175). Myocyte contractility was measured by computer-aided videomicroscopy. RESULTS: Cardioplegic arrest and rewarming reduced myocyte shortening velocity compared with normothermic control (25.3 +/- 2.5 microm/s versus 50.9 +/- 1.4 microm/s, p < 0.05). Adenosine-augmented cardioplegic arrest improved myocyte contractility with rewarming in a concentration-dependent fashion. For example, cardioplegia augmented with 10 micromol/L adenosine improved myocyte shortening velocity by 33% (33.6 +/- 3.0 microm/s versus 25.3 +/- 2.5 microm/s, p < 0.05), whereas 200 micromol/L adenosine improved shortening velocity by 97% (49.9 +/- 3.4 microm/s vs 25.3 +/- 2.5 microm/s, p < 0.05) compared with conventional cardioplegia. CONCLUSIONS: This study demonstrated concentration-dependent protective effects of adenosine-augmented cardioplegia on myocyte contractile function with subsequent reperfusion and rewarming. These results suggest that stimulation of putative myocyte adenosine receptors may provide enhanced protective effects on myocyte contractile processes during cardioplegic arrest.

Adenosine↗

Differential effects of novel protamine variants on myocyte contractile function with left ventricular failure.

BACKGROUND: Protamine administration can cause left ventricular (LV) dysfunction, which may have clinical significance in the setting of congestive heart failure (CHF). Protamine variants have recently been constructed with heparin reversal capacity similar to protamine. The purpose of this study was to examine the potential differential effects of these protamine variants on isolated myocyte contractile function in normal myocytes and in myocytes after the development of CHF. METHODS: Contractile function was measured by means of computer-aided videomicroscopy in myocytes from five normal pigs and five pigs with CHF induced by rapid pacing (240 beats/min for 3 weeks). Myocyte contractility was examined in the presence of 40 micrograms/ml native protamine or one of three protamine variants: (1) reduced charge (+18) and lysine substituted for arginine; (2) lysine-substituted variant with glutamic acid substituted for the initial proline; or (3) arginine-rich peptide with a terminal arginine-glycine-aspartic acid (RGD) amino acid sequence. RESULTS: In the presence of native protamine, myocyte percent shortening fell from baseline in both the normal (2.86 +/- 0.15 versus 4.58 +/- 0.08, p < 0.05) and the CHF groups (1.01 +/- 0.06 versus 2.07 +/- 0.05, p < 0.05). With both of the lysine-substituted protamine variants, percent shortening fell from baseline in the normal group (3.42 +/- 0.20 for arginine and 3.74 +/- 0.20 for glutamic acid versus 4.58 +/- 0.08, p < 0.05), and was unchanged in the CHF group (1.94 +/- 0.13 versus 2.07 +/- 0.05, p = 0.34 for arginine; and 1.96 +/- 0.10 versus 2.07 +/- 0.05, p = 0.31, for glutamic acid). However, with the arginine/RGD variant, percent shortening fell from baseline in both the normal (2.86 +/- 0.23 versus 4.58 +/- 0.08, p < 0.05) and the CHF groups (1.32 +/- 0.10 versus 2.07 +/- 0.05, p < 0.05). CONCLUSIONS: Specific changes in the primary and secondary structures of protamine had different effects on myocyte contractile function. Furthermore, the negative effects of lysine-substituted protamine variants on myocyte contractility were less pronounced in both CHF and normal myocytes. Thus protamine variants may be of clinical use, particularly in the setting of preexisting LV dysfunction.

Animals↗

The carboxyl-terminal zinc-binding domain of the human papillomavirus E7 protein can be functionally replaced by the homologous sequences of the E6 protein.

The carboxyl-terminus is necessary for the functional and structural integrity of the human papillomavirus (HPV) E7 oncoprotein. Since many mutations in this domain of E7 result in the formation of unstable proteins, we have evaluated the importance of this region by replacing it with structurally related domains derived from HPV E6 proteins. Biological analysis of these mutant chimeric E7/E6 proteins showed that they retained E7-specific biological activities including cooperation with the ras oncogene to transform primary baby rat kidney cells and transcriptional activation of an E2F responsive reporter plasmid. One of the chimeric proteins was impaired in its ability to physically disrupt pRB/E2F complexes in vitro suggesting that there are defined molecular determinants in the carboxyl-terminus of E7 for this activity. In contrast, none of these proteins exhibited E6-like properties including binding to p53 and/or degradation of associated proteins.

Amino Acid Sequence↗

Pulmonary hemodynamics and endothelin levels in pacing-induced heart failure: during rest and exercise.

Elevated plasma levels of endothelin (ET) have been reported to accompany the development of heart failure (HF), and therefore, this potent vasoconstrictive peptide has been postulated to contribute to the altered pulmonary hemodynamics that occur in this disease process. The overall goal of this study was to examine more carefully the relationship between ET levels in the pulmonary system and pulmonary hemodynamics in the normal and HF states, during both rest and exercise. This study used a porcine model of chronic rapid pacing that has been shown in previous studies to produce left ventricular dysfunction and neurohormonal system activation consistent with the syndrome of HF. Pigs (n = 10) were chronically instrumented to measure pulmonary and systemic hemodynamics, parenchymal flow, and ET content and to obtain blood samples from the pulmonary circuit in the conscious state. Measurements were performed in the normal control state and again following the development of pacing-induced HF (240 beats/min per 21 days), both at rest and during treadmill exercise (3 mph, 15 degrees incline, 12 minutes). With HF, under ambient resting conditions, a threefold increase in pulmonary plasma ET occurred and was accompanied by a fivefold increase in pulmonary vascular resistance. During treadmill exercise, pulmonary plasma ET and pulmonary vascular resistance remained elevated in the HF group when compared with the normal state and were associated with a sixfold decrease in pulmonary parenchymal flow. Pulmonary parenchymal ET content was increased with HF when compared with values for normal control subjects (8.5 +/- 0.6 vs 5.6 +/- 0.8 fmol ET/mg protein, P < .05). Thus, the findings of this study suggest that in this model of HF, increased ET within the pulmonary circuit contributed to abnormalities in resistive properties and parenchymal flow.

Animals↗

Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance.

Oral administration of protein can induce antigen-specific immune hyporesponsiveness. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plants may be ideally suited for this purpose, as they can synthesize, glycosylate and assemble mammalian proteins to provide huge quantities of relatively low cost soluble proteins. Furthermore, edible transgenic plants could provide a simple and direct method of autoantigen delivery for oral tolerance. Therefore, the aim of this study was to determine whether a transgenic plant expression system was capable of synthesizing the diabetes-associated autoantigen, glutamic acid decarboxylase (GAD) in an immunogenic form and whether the oral administration of an autoantigen expressed by a plant could directly induce protective immune responses in a mouse model of diabetes. We show that a GAD-expressing transgenic plant, given as a dietary supplement, inhibits the development of diabetes in the non-obese diabetic (NOD) mouse.

Agrobacterium tumefaciens↗

Hypogammaglobulinaemia occurs in Fas-deficient MRL-lpr mice following deletion of MHC class II molecules.

Fas (CD95)-mediated apoptosis in B and T cells is deficient in both human autoimmune lymphoproliferative syndrome and in MRL-lpr mice, a model for systemic lupus erythematosis (SLE). Autoimmune disease in these mice is associated with polyclonal B cell activation, increased serum immunoglobulin and autoantibodies. In non-autoimmune mice MHC class II is not required for normal serum immunoglobulin expression, and previously we have shown using MHC class II-deficient MRL-lpr mice (MRL-lpr Ab-/-) that generation of specific antibodies to DNA requires MHC class II-directed T cell help. In contrast, in the present study we demonstrate that MRL-lpr Ab-/- mice also have a profound reduction of total serum immunoglobulin levels, suggesting abnormal polyclonal regulation of B cells by MHC class II-directed T cells occurs in the autoimmune MRL-lpr strain. This abrogation of immunoglobulin production does not occur in MHC class II-deficient non-obese diabetic (NOD) mice, nor in MHC class I-deficient NOD or MRL-lpr mice. Reduced immunoglobulin levels in MRL-lpr Ab-/- mice were not due to a lack of B cells or to an increased loss of circulating immunoglobulin, but were associated with reduced numbers of surface IgG-positive B cells. These results define a general abnormal regulation of B cells in MRL-lpr mice through a process requiring MHC class II, and suggest that Fas deficiency may allow expansion of totally T-dependent B cells.

Agammaglobulinemia↗

Angiotensin II subtype-1 receptor blockade during the development of left ventricular hypertrophy in dogs: effects on ventricular and myocyte function.

Inhibition of the angiotensin-converting enzyme (ACE) in developing left ventricular (LV) hypertrophy has been demonstrated to have inhibitory effects on myocardial growth. An important mechanism of action of ACE inhibition is modulation of myocardial AT1 Ang II-receptor activity. However, whether and to what extent AT1 Ang II-receptor blockade may influence LV and myocyte function during the hypertrophic process remains unclear. Accordingly, our project examined the relation between changes in LV and myocyte function during the LV hypertrophic process that occurs after recovery from long-term rapid pacing. Dogs were randomly assigned to the following treatment groups: (a) Pace and Recovery, long-term rapid pacing (4 weeks; 216 +/- 2 beats/min) followed by a 4-week recovery period (n = 6); (b) Recovery/AT1 Block, concomitant AT1 Ang II-receptor blockade [irbesartan (SR 47436; BMS-186295) 30 mg/kg b.i.d.] administered during the 4-week recovery period (n = 5); and (c) Control, sham controls (n = 6). There was no difference in mean arterial pressure in any of the three groups. With pacing and recovery, LV end-diastolic volume and mass were increased by >50% from control values. The significant LV remodeling that occurred with recovery from long-term rapid pacing was associated with a decline in LV ejection fraction (59 +/- 3% vs. 68 +/- 4%) and myocyte velocity of shortening (43 +/- 3 microm/s vs. 63 +/- 3 microm/s) when compared with controls (p < 0.05). With recovery from long-term rapid pacing, LV myocyte length (176 +/- 6 microm vs. 150 +/- 1 microm) and cross-sectional area were increased (292 +/- 7 microm2 vs. 227 +/- 6 microm2) compared with controls (p < 0.05). With AT1 Ang II block during recovery from rapid pacing, LV end-diastolic volume was similar to untreated recovery values, but LV mass was normalized. LV ejection fraction was not different from control values with AT1 Ang II-receptor block. Steady-state myocyte velocity of shortening with AT1 Ang II block was similar to control values (55 +/- 5 microm/s), but percentage shortening remained reduced from control (3.55 +/- 0.37% vs. 4.71 +/- 0.12%, respectively, p < 0.05) and was similar to untreated recovery (3.59 +/- 0.23%). With AT1 Ang II block, myocyte length was similar to untreated recovery values, but cross-sectional area was reduced (260 +/- 5 microm2, p < 0.05). Thus AT1 Ang II-receptor blockade instituted in this model of developing LV hypertrophy, significantly reduced LV mass but did not reduce the degree of LV dilation. The cellular basis for these effects of AT1 Ang II-receptor blockade included persistent abnormalities in LV myocyte geometry. AT1 Ang II-receptor blockade improved certain indices of myocyte contractile function from untreated hypertrophy values. These findings suggest that in this pacing-recovery model, the development of LV hypertrophy and myocyte contractile dysfunction may be caused, at least in part, by AT1 Ang II-receptor activation.

Angiotensin Receptor Antagonists↗