Fiix-prothrombin time monitoring improves warfarin anticoagulation outcome in atrial fibrillation: a systematic review of randomized trials comparing Fiix-warfarin or direct oral anticoagulants to standard PT-warfarin.

BACKGROUND: Monitoring warfarin with Fiix-prothrombin time (Fiix-PT), which is only affected by coagulation factors II and X, stabilizes anticoagulation and reduces thromboembolism compared to PT/INR monitoring. We compared outcome in nonvalvular atrial fibrillation (NVAF) patients treated with Fiix-warfarin, direct oral anticoagulants (DOACs), or PT-warfarin. METHODS: A systematic efficacy and safety assessment by retrieving data from the Fiix trial and the four major phase III DOAC trials in NVAF. Prespecified outcomes included stroke and systemic embolism (SSE), SSE and myocardial infarction (MI), major bleeding (MB), composite major vascular events (SSEMI and MB; CMVE), and deaths. We calculated relative risk, 95% CI, and 95% confidence limits (CL) for each outcome and performed meta-analysis using fixed- and random-effects modeling. RESULTS: There were 613 and 628 observation years with Fiix-warfarin and PT-warfarin in the Fiix trial, and 70 628 and 57 962 with DOACs and PT-warfarin in DOAC trials. Populations were comparable although death rates were lower in the Fiix trial. Compared to pooled PT-warfarin, Fiix-warfarin reduced SSE (RR 0.54;95% CI 0.26-1.10/95% CL <1.00), SSEMI (0.51;0.26-0.99/<0.90), MB (RR 0.63;0.37-1.07/<0.99), and CMVE (RR 0.66;0.43-1.00/<0.94). Vascular death was lower (RR 0.13;0.04-0.47/<0.42). Compared to pooled DOACs, Fiix-warfarin consistently had lower point estimates for the RR for efficacy and safety, but only significant for lower death rates (vascular death RR 0.14;0.04-0.49/<0.43). Meta-analysis comparing Fiix-warfarin and DOACs with PT-warfarin consistently found Fiix-warfarin to have the lowest point estimates for efficacy. CONCLUSION: Monitoring warfarin with Fiix-PT reduces risk of vascular events in NVAF patients as much as DOACs. Warfarin monitored with Fiix-PT is an improved anticoagulant.

Plasma 25-hydroxyvitamin D2 and D3 levels and incidence of postoperative atrial fibrillation.

Low circulating levels of total 25-hydroxyvitamin D (25(OH)D) have been associated with an increased risk of adverse effects after cardiac surgery. The metabolites, 25(OH)D2 and 25(OH)D3, provide a good index of vitamin D status. In this study, we examined the association between preoperative plasma levels of total 25(OH)D, 25(OH)D2 and 25(OH)D3 and the risk of postoperative atrial fibrillation (POAF) following open heart surgery. The levels of plasma 25(OH)D2 and 25(OH)D3 in 118 patients, who underwent coronary artery bypass grafting and/or valvular surgery, were measured immediately prior to surgery and on postoperative day 3 by liquid chromatography-tandem mass spectrometry. Patients who developed POAF had higher median plasma levels of 25(OH)D2 than those who remained in sinus rhythm (SR) (P = 0·003), but no significant difference was noted in levels of 25(OH)D3 or total 25(OH)D between the two groups (P > 0·05). By univariate analysis, patients with total 25(OH)D and 25(OH)D2 levels above the median had higher frequency of POAF (P < 0·05) and the incidence of POAF increased significantly with each higher quartile of preoperative plasma levels of 25(OH)D2 (P = 0·001), an association that was independent of confounding factors. In both the SR and POAF groups, the median plasma levels of 25(OH)D2, 25(OH)D3 and total 25(OH)D were lower (P < 0·05) on the third postoperative day compared with preoperatively. Our findings demonstrate that higher plasma levels of 25(OH)D2 are associated with increased risk of POAF, while this is not the case for 25(OH)D3 or total 25(OH)D. The reason for these discrepant results is not clear but warrants further study.

U-shaped relationship between tissue docosahexaenoic acid and atrial fibrillation following cardiac surgery.

BACKGROUND/OBJECTIVES: Randomised controlled trials (RCTs) evaluating the effect of fish oil supplementation on postoperative atrial fibrillation (POAF) following cardiac surgery have produced mixed results. In this study, we examined relationships between levels of red blood cell (RBC) n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and the incidence of POAF. SUBJECTS/METHODS: We used combined data (n=355) from RCTs conducted in Australia and Iceland. The primary end point was defined as POAF lasting >10 min in the first 6 days following surgery. The odds ratios (ORs) for POAF were compared between quintiles of preoperative RBC n-3 LC-PUFA levels by multivariable logistic regression. RESULTS: Subjects with RBC docosahexaenoic acid (DHA) in the fourth quintile, comprising a RBC DHA range of 7.0-7.9%, had the lowest incidence of POAF. Subjects in the lowest and highest quintiles had significantly higher risk of developing POAF compared with those in the fourth quintile (OR=2.36: 95% CI; 1.07-5.24 and OR=2.45: 95% CI; 1.16-5.17, respectively). There was no association between RBC eicosapentaenoic acid levels and POAF incidence. CONCLUSIONS: The results suggest a 'U-shaped' relationship between RBC DHA levels and POAF incidence. The possibility of increased risk of POAF at high levels of DHA suggests an upper limit for n-3 LC-PUFAs in certain conditions.

Inflammatory response following heart surgery and association with n-3 and n-6 long-chain polyunsaturated fatty acids in plasma and red blood cell membrane lipids.

BACKGROUND: Open heart surgery is associated with a systemic inflammatory response. The n-3 long-chain polyunsaturated fatty acids (LC-PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the n-6 LC-PUFA arachidonic acid (AA) may contribute to modulation of the inflammatory response. OBJECTIVE: We investigated whether the preoperative levels of EPA, DHA and AA in plasma phospholipids (PL) and red blood cell (RBC) membrane lipids in patients (n=168) undergoing open heart surgery were associated with changes in the plasma concentration of selected inflammatory mediators in the immediate postoperative period. RESULTS AND CONCLUSIONS: The postoperative concentration of TNF-ß was lower (P<0.05) and those of hs-CRP, IL-6, IL-8, IL-18 and IL-10 higher (P<0.05) than the respective preoperative concentrations. We observed that the preoperative levels of EPA and AA in plasma PL and RBC membrane lipids were associated with changes in the concentration of pro-inflammatory and anti-inflammatory mediators, suggesting a complex role in the postoperative inflammatory process.

Ibutilide for treatment of atrial fibrillation in the emergency department.

The purpose of this study was to assess the efficacy and safety of ibutilide, a class III antiarrhythmic drug, for acute treatment of atrial fibrillation (AF) in the emergency department (ED) setting. A retrospective analysis was done reviewing all patients with AF who received ibutilide in the ED in a university hospital setting. A total of 22 patients received ibutilide. Another 24 patients who received rate control drugs only served as a control group. Of the 22 patients who received ibutilide, 14 (64%) converted to sinus rhythm. The mean (SD) rate of AF was 137 (24) bpm and the mean QTc interval immediately after conversion to sinus rhythm was 420 (28) ms. There were no complications. In the rate control group 7 patients (29%) converted to sinus rhythm (p<0.05, compared with ibutilide). The mean rate of AF was 126 (26) bpm (p = ns, compared with ibutilide) and the mean QTc interval in those who converted was 377 (28) ms (p<0.05, compared with ibutilide). One patient developed severe bradycardia. Ibutilide is effective for conversion of recent onset AF in patients presenting to the ED and there is a low rate of complications from ibutilide in this setting.

Prevention of ischemic ventricular tachycardia of Purkinje origin: role for alpha(2)-adrenoceptors in Purkinje?

Recent studies have shown the presence of postjunctional alpha(2)-adrenergic receptors on canine Purkinje fibers but not muscle cells. Stimulation of these receptors results in prolongation of the action potential duration and the Purkinje relative refractory period. We studied the effect of alpha(2)-adrenergic agonists on inducible ischemic ventricular tachycardia (VT) of both Purkinje fiber and myocardial origin. Open-chest dogs in whom VT was induced with extrastimuli after occlusion of the anterior descending coronary artery were studied. A mapping system, incorporating Purkinje signals, characterized the mechanisms of VT. The alpha(2)-adrenergic agonists clonidine (0.5-4.0 microg/kg) or UK 14,304 (4-5 microg/kg) versus saline were given intravenously after reproducibility of inducible sustained monomorphic VT had been demonstrated. Eighteen dogs were given clonidine, eleven of which had focal Purkinje VT. Of these 11 dogs, clonidine blocked VT induction in 9 (81.9%) and rendered VT nonsustained in 1 (9.1%), and VT remained inducible in 1 dog (9.1%), although this was focal midmyocardial VT only. In the seven dogs with VT of myocardial origin, six (85.6%) remained inducible with clonidine, whereas one dog (14.4%) had only nonsustained VT after clonidine. Of the six dogs, UK 14,304 blocked VT induction in four (66.6%) and rendered VT nonsustained in one (16.7%), and VT remained inducible in one dog (16.7%). In four dogs with VT of myocardial origin, VT remained inducible. In the eight control dogs that were given saline, focal Purkinje VT was repeatedly inducible. Pharmacological stimulation of postjunctional alpha(2)-adrenoceptors on Purkinje fibers may selectively prevent induction of VT of Purkinje fiber origin in the ischemic canine ventricle.

[Attitude of the Icelandic population towards performing cardiopulmonary resuscitation on strangers in the pre-hospital setting.].

OBJECTIVE: Initiation of bystander cardiopulmonary resuscitation (CPR) is directly linked to the outcome of cardiac arrest in the community. Recent reports have indicated a reluctance among witnesses to perform CPR on strangers especially mouth to mouth ventilation. The status of this in Iceland is unknown. The objective of this study was to assess the attitude of Icelanders towards bystander CPR. MATERIAL AND METHODS: A telephone survey was conducted on 1200 randomly selected Icelanders, aged 16-75 years, with regard to their attitude towards pre-hospital CPR on strangers. A total of 804 (70.1%) chose to participate. RESULTS: A large number had received some kind of training in CPR (73%), wheras only 6% had actually participated in CPR. In accordance, 50% thought they would be able to perform chest compressions adequately and 55% mouth to mouth ventilation. A total of 491 (65%) would likely volunteer to perform chest compressions on a stranger, while 178 (24%) would not and 84 (11%) were undecided. Similarly, 473 (64%) would likely volunteer to perform mouth to mouth ventilation on a stranger. One hundred seventy seven (24%) would not and 93 (12%) were unsure. An overwhelming majority, 620 (81%) said it would not make any difference regarding their participation in CPR if the procedure was simplified and included only chest compressions but not mouth to mouth ventilation. CONCLUSIONS: Icelanders have a very positive attitude towards bystander CPR, over two thirds have had some kind of CPR instruction and a large majority has no aversion towards performing mouth to mouth ventilation on strangers. These results are in contrast to similar data from the United States.

Cerebral embolism resulting from a transvenous pacemaker catheter inadvertently placed in the left ventricle: a report of two cases confirmed by echocardiography.

BACKGROUND: Transvenous pacemaker catheters may be placed unintentionally into the left ventricle. This can lead to thromboembolic complications. METHODS AND RESULTS: We report two cases where pacemaker catheters placed unintentionally in the left ventricle via a patent foramen ovale resulted in cerebrovascular accidents. The malpositioned pacemaker catheters were demonstrated by transthoracic and transesophageal echocardiography. In both patients, no further embolic events have occurred after treatment, which in one case consisted of pacemaker catheter removal and in the other case, anticoagulation. CONCLUSION: Echocardiography can be useful to confirm inadvertent left ventricular pacemaker placement in patients with pacemakers who have cerebrovascular accidents.

[Atrial fibrillation: therapeutic options at the turn of the century.].

Atrial fibrillation is an increasing health care problem and the incidence of this arrhythmia is expected to increase substantially in the next two decades. Atrial fibrillation can be seen in patients with structural heart disease as well as those who have a normal heart. A variety of underlying mechanisms can lead to atrial fibrillation, including parasympathetic stimulation causing vagal atrial fibrillation. Complications of atrial fibrillation include congestive heart failure and stroke. Atrial fibrillation is an independent risk factor for increased mortality. In recent years a number of new treatment options have emerged. Anticoagulation decreases the risk of stroke and new antiarrhythmic drugs have been developed which increase the likelihood of conversion to and subsequent maintenance of sinus rhythm. In addition there have been advances in the approach to electrical cardioversion. Radiofrequency ablation therapy is a promising option in the treatment of atrial fibrillation and could be increasingly utilized in the near future. This paper focuses on advances in the therapy of atrial fibrillation, including new pharmacological agents, radiofrequency ablation and electrical cardioversion.

Electrophysiologic effects of civamide (zucapsaicin) on canine cardiac tissue in vivo and in vitro.

The cardiac electrophysiologic effects of civamide (zucapsaicin), the cis-isomer of the alkyl vanillylamide, capsaicin, were evaluated in intact dogs and isolated Purkinje fibers. In anesthetized dogs, the mechanism of ventricular tachycardia inducible from 1 to 3 h after coronary artery occlusion was determined by activation mapping. Of 16 dogs studied, nine had ventricular tachycardia of focal endocardial origin; four, a reentrant mechanism; and three had no inducible arrhythmia. Civamide (50 microg/kg) was administered to 10 of 13 dogs that were inducible, but three dogs were used as time controls. Transmural activation times were unaltered by civamide, but mean arterial pressure decreased from 76 +/- 10 to 66 +/- 10 mm Hg (p < 0.05), and muscle refractory periods shortened from 138 +/- 3 to 132 +/- 4 ms (p < 0.05). Civamide altered inducibility in five of six dogs with ventricular tachycardia of focal endocardial origin, but those with epicardial reentrant mechanisms were not affected in three of four dogs. With microelectrode techniques in vitro, civamide (10(-5) M) shortened the action-potential duration at 50% repolarization (APD50) from 193 +/- 13 to 177 +/- 12 ms (p < 0.01) and APD90 from 260 +/- 15 to 248 +/- 13 ms (p < 0.01) in isolated Purkinje fibers (n = 10). Nifedipine prevented the effects of civamide in vitro. These results show that civamide may alter inducibility of ventricular tachycardia with focal endocardial origin and shorten APD of Purkinje fibers in vitro. The effects of civamide in vitro are prevented by preexposure of the Purkinje fibers to nifedipine, suggesting that the electrophysiologic effects of civamide may be mediated through blockade of calcium channels.

Role of the Purkinje system in spontaneous ventricular tachycardia during acute ischemia in a canine model.

BACKGROUND: A role for the Purkinje system in the development of spontaneous ventricular tachycardia (VT) during acute ischemia has been suspected but not proved. We used a three-dimensional activation mapping system incorporating Purkinje signals to characterize the mechanism and site of origin of spontaneous VT occurring in the first 30 minutes after coronary artery occlusion in a dog model. METHODS AND RESULTS: The left anterior descending coronary artery was occluded in 48 dogs after instrumentation of the risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms through the myocardial wall. VT of Purkinje origin was defined as a focal endocardial VT with a Purkinje potential identified before muscle potential on the electrode recording the earliest activity. Purkinje potentials were identified on an average of 10 of the 21 plunge needles. During atrial pacing at cycle lengths of 300 to 700 ms, a total of 25 VTs were observed from 18 of the 48 dogs (37.5%). Of the VTs, 15 (60.0%) were of focal Purkinje origin, 1 (4.0%) of focal endocardial origin, 2 (8.0%) of focal midmyocardial origin, and 2 (8.0%) of focal epicardial origin; 3 (12.0%) had a reentrant mechanism, whereas in 2 (8.0%), the mechanism could not be defined. The mean cycle length of all VTs was 265+/-17 ms (mean+/-SEM, n=25). Of the 25 VTs, 19 originated from an ischemic area as defined by significant decreases in voltages of muscle electrograms at the time of occurrence of the VT, 4 originated from an ischemic border zone, and the origin of 2 could not be determined. CONCLUSIONS: In this model, VT with a focal mechanism is commonly seen in the early ischemic period. Sixty percent of the VTs were of focal Purkinje origin as characterized by three-dimensional activation mapping. The results of this study indicate that Purkinje tissue may play an important role in the development of early ischemic VT.

Mechanism of alpha-2 adrenergic modulation of canine cardiac Purkinje action potential.

We reported recently that stimulation of postjunctional alpha-2 adrenergic receptors prolongs the action potential durations (APD) of isolated canine Purkinje fibers. With standard microelectrode techniques, we examined the ionic mechanism through which alpha-2 adrenergic stimulation prolonged Purkinje APD, by measuring the effects of inhibitors of the various plateau currents on the alpha-2-mediated prolongation of APD. The alpha-2-specific agonist UK 14,304 (0.1 microM) prolonged the Purkinje APD at 50% repolarization and the APD at 90% repolarization, and these effects were inhibited by yohimbine (0.1 microM). The Purkinje APD at 50% repolarization and the APD at 90% repolarization were prolonged significantly with the transient outward potassium current inhibitor 4-aminopyridine (1 mM), the rapid component of delayed rectifier potassium current inhibitor d-sotalol (10 microM), the slow component of delayed rectifier potassium current inhibitor indapamide (0.1 microM) and the chloride current inhibitor mefenamic acid (10 nM) and were shortened significantly with the calcium current inhibitor nifedipine (0.3 microM). Prolongation of Purkinje APD at 50% repolarization and APD at 90% repolarization by UK 14,304 remained intact in the presence of d-sotalol, indapamide, mefenamic acid and nifedipine. All of these UK 14,304 effects were significantly reversed by yohimbine. Only in the presence of 4-aminopyridine did UK 14,304 fail to prolong Purkinje APD. The phase 1 magnitudes of Purkinje action potentials were also significantly inhibited by UK 14,304. This effect was completely abolished only in the presence of 4-aminopyridine. These results suggest that inhibition of the 4-aminopyridine-sensitive transient outward potassium current is the major ionic mechanism by which alpha-2 adrenergic stimulation prolongs Purkinje APD.

Factors predicting maintenance of sinus rhythm after direct current cardioversion of atrial fibrillation and flutter: a reanalysis with recently acquired data.

A prospective study was conducted to evaluate how many patients maintain normal sinus rhythm after direct current (DC) cardioversion of atrial arrhythmias and to assess factors predictive of long-term success. The study group consisted of 61 patients (45 men) aged 18-88 years (mean age 66 +/- 11 years) who underwent cardioversion at our department from October 1990 to June 1992. Prior to cardioversion, the patients' medical history, medications, heart size on chest X ray, and echocardiographic findings were reviewed. Overall, 41 (67.2%) patients were in atrial fibrillation, while 20 (32.8%) had atrial flutter. Only 15% of the patients had valvular heart disease. Sinus rhythm was restored by DC cardioversion in 47 (77%) patients, none of whom experienced an embolic event prior to discharge. Patients with atrial flutter had a higher conversion rate (95%) than those in atrial fibrillation (68.3%; p = 0.024), and also patients with an arrhythmia for less than 1 week (94.4%) compared to those with a longer or unknown duration (69.8%; p = 0.047). The primary success rate was not influenced by heart size on chest X ray or echocardiographic variables. The study protocol aimed at following up the patients for 1 year after cardioversion. Of the 47 patients who converted to sinus rhythm data are available on 44 for a mean follow-up of 11 +/- 3 months (range 1-14 months), at which time 25 (57%) still remained in sinus rhythm. Heart size on the chest X ray was significantly increased in the group that did not maintain sinus rhythm (p = 0.03) and their left atrial size on echocardiography was slightly increased (p = 0.10). Patients who originally had atrial flutter were more likely to remain in sinus rhythm than those who had been in atrial fibrillation (p = 0.12), as did patients with an arrhythmia for less than 1 week prior to cardioversion in comparison to those with a longer or unknown duration (p = 0.11). Thus, in contrast to previous reports, according to these recent data on a patient population with a low prevalence of valvular heart disease, DC cardioversion can be attempted in most patients with atrial tachyarrhythmias. Clinical factors, heart size on chest X ray and echocardiographic findings should, however, be considered before deciding to perform DC cardioversion.

[Factors predicting long-term success of DC cardioversion of atrial arrhythmias.].

A prospective study was conducted to evaluate how many patients maintain sinus rhythm after DC cardioversion of atrial arrhythmias and to assess factors predictive of long-term success. The study group consisted of 61 patients (45 men, 16 women) aged 18-88 years (mean age 66 +/- 11 years) who undervent cardioversion, at the Department of Cardiology, Landspitalinn, from October 1990 to June 1992. Prior to cardioversion data were collected on the patient's medical history, medications, heart size on chest X-ray, and echocardiographic findings. Overall, 41 (67.2%) patients were in atrial fibrillation while 20 (32.8%) had atrial flutter. Sinus rhythm was restored by DC cardioversion in 47 (77%) patients, none of whom experienced an embolic event prior to discharge. Patients with atrial flutter had a higher conversion rate (95%) than those in atrial fibrillation (68.3%) (p=0.024) and also those who had had an atrial arrhythmia for less than one week (94.4%) in comparison to patients with an arrhythmia of longer or unknown duration (69.8%) (p-0.047). The primary success rate was not influenced by heart size on chest X-ray or echocardiographic variables. The study aimed to follow the patients for one year after cardioversion. Of the 47 patients who converted to sinus rhythm data are available on 44 for a mean follow-up of 11 +/- 3 months (range 1-14 months), at which time 25 (57%) still remained in sinus rhythm. Heart size on chest X-ray was significantly increased in the group that did not maintain sinus rhythm (p=0.03), and their left atrial size on echocardiography was slightly increased (p=0.10). Patients who originally had atrial flutter were more likely to remain in sinus rhythm than those who had been in atrial fibrillation (p=0.12), as did those who had had the arrhythmia for less than one week prior to cardioversion compared to those who had a longer or unknown duration (p=0.11). We conclude, that DC cardioversion can be attempted in most patients with atrial flutter or fibrillation. However, clinical factors, heart size on chest X-ray and echocardiographic findings should be considered before deciding to perform DC cardioversion.

Renovascular hypertension and coronary heart disease complicating essential thrombocythemia.

A 36-year-old male was evaluated for treatment-resistant hypertension. A high platelet count 828 x 10(9).l-1, led to the diagnosis of essential thrombocythemia (ET). Aorto-renal angiography revealed critical bilateral renal artery stenosis and coronary angiography showed three-vessel disease. Percutaneous transluminal renal angioplasty was only partially successful. The patient received a 12-week course of busulphan and subsequently the thrombocyte count decreased to 200 x 10(9).l-1. Renal angiography 12 months later showed bilateral regression of the renal artery stenosis with lowering of the blood pressure to normal levels.

Cancer of the pancreas in Iceland. An epidemiologic and clinical study, 1974-85.

A retrospective study was performed of all patients diagnosed as having pancreatic cancer in Iceland during the period 1974-85 (12 years). The incidence of the disease during the period according to this study was 10.7 per 100,000 males and 9.8 per 100,000 females, with age-adjusted world standard incidences of 9.0 per 100,000 males and 6.7 per 100,000 females. A total of 301 patients were identified; adequate information could be obtained for 281 patients, and 225 (74.8%) had the diagnosis histologically confirmed. Two hundred and five patients with adenocarcinoma were accepted for detailed analysis. Of the patients with adenocarcinoma 139 (67.8%) were diagnosed at laparotomy, and 33 of them had the tumour resected, with an operative mortality of 12.1%. The cancer was located in the head of the pancreas in 102 patients (49.8%), and in 159 (77.6%) metastases were found at the time of diagnosis. The median survival time for the patients with adenocarcinoma was 95.4 days (SD +/- 11.1 days), although there were two patients in this group who were alive 5 years after diagnosis. The median survival for the total group of 281 patients was 98.3 days (SD +/- 11.0 days), although 6 of these patients lived for more than 5 years. The percentage of histologically confirmed tumours in Iceland is high compared with many previously reported studies.

Primary cytomegalovirus infection and gastric ulcers in normal host.

A 42-year-old woman presented with epigastric pain and vomiting. Upper gastrointestinal endoscopy revealed three gastric ulcers. Histologic examination of biopsies from the ulcers showed cytomegalovirus inclusion bodies. The appearance of IgM antibodies to cytomegalovirus indicated a recent and primary infection. Stored serum from her last pregnancy 17 months previously contained no cytomegalovirus antibodies. A thorough evaluation of her immune system revealed no abnormality. We are aware of only two other cases where seroconversion was documented in normal hosts. Cytomegalovirus infections in the gastrointestinal tract of normal hosts are very unusual but a common cause of morbidity in immunocompromised hosts. We believe that cytomegalovirus may have a role in the pathogenesis of gastrointestinal lesions in nonimmunocompromised patients.