Case Report: Azathioprine: An Old and Wronged Immunosuppressant.

Mycophenolate rapidly substituted azathioprine (AZA) in transplant immunosuppression regimens since the 1990s, when early clinical trials indicated better outcomes, although opposite results were also observed. However, none of these trials used the well-established optimization methods for AZA dosing, namely, thiopurine methyltransferase pharmacogenetics combined with monitoring of the thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Resistance to optimize AZA therapy remains today in transplant therapy, despite the fact that thiopurine metabolite testing is being used by other medical disciplines with evident improvement in clinical results. In a previous analysis, we found that active 6-TGN metabolites were not detectable in about 30% of kidney transplant patients under continuous use of apparently adequate azathioprine dosage, which demonstrates the need to monitor these metabolites for therapeutic optimization. Two of four case studies presented here exemplifies this fact. On the other hand, some patients have toxic 6-TGN levels with a theoretically appropriate dose, as seen in the other two case studies in this presentation, constituting one more important reason to monitor the AZA dose administered by its metabolites. This analysis is not intended to prove the superiority of one immunosuppressant over another, but to draw attention to a fact: there are thousands of patients around the world receiving an inadequate dose of azathioprine and, therefore, with inappropriate immunosuppression. This report is also intended to draw attention, to clinicians using thiopurines, that allopurinol co-therapy with AZA is a useful therapeutic pathway for those patients who do not adequately form active thioguanine metabolites.

COVID-19 and Cytomegalovirus Co-infection: A Challenging Case of a Critically Ill Patient with Gastrointestinal Symptoms.

COVID-19 is a severe disease that has reached pandemic status. To the best of our knowledge, we describe the first case of COVID-19 and cytomegalovirus (CMV) co-infection in a critically ill patient. We discuss the challenge of establishing the diagnosis as well as the management of tissue-invasive gastrointestinal CMV infection (TI-GI CMV) simulating vascular involvement and intestinal obstruction in a critically ill patient. LEARNING POINTS: We describe a case of COVID-19 and cytomegalovirus (CMV) co-infection in a critically ill patient.Clinical symptoms simulated mesenteric vascular involvement and intestinal obstruction.The successful management of invasive CMV colitis in a patient with COVID-19 with atypical symptoms is described.

Fluid overload is associated with use of a higher number of antihypertensive drugs in hemodialysis patients.

INTRODUCTION: Hypertension is multifactorial, highly prevalent in the hemodialysis (HD) population and its adequate control requires, in addition to adequate volume management, often the use of multiple antihypertensive drugs. We aimed to describe the use of antihypertensive agents in a group of HD patients and to evaluate the factors associated with the use of multiple classes (≥3) of antihypertensives. METHODS: We analyzed the baseline data from the HDFit study. Clinically stable patients with HD vintage between 3 and 24 months without any severe mobility limitation were recruited from sites throughout southern Brazil. Fluid status was measured pre-dialysis with the Body Composition Monitor (BCM; Fresenius, Germany). Fluid overload (FO) was considered when the overhydration index (OH) was greater than 7% of extracellular water (OH/ECW > 7%) and overweight was defined as a body mass index (BMI) greater than 25 kg/m2 . Prescriptions of antihypertensive drugs were obtained from participants' reports and medical records. Logistic regression was employed to determine factors associated with excessive use of antihypertensive medication (≥3 classes). FINDINGS: Of 195 studied patients, 171 with complete data were included (70% male, 53 ± 15 years old, 57% of them with FO). Pre-dialysis systolic blood pressure (SBP) was 150 ± 24 mmHg and patients used a median of 2 (1-3) antihypertensive drugs. Vasodilators (20%) were of lowest prevalence, use of other classes varied from 40% to 53%. Sixty-two (36%) subjects used ≥3 classes and presented a higher prevalence of diabetes and FO, lower prevalence of overweight, and higher SBP. In a logistic regression model age, BMI <25 kg/m2 , and OH/ECW > 7% were associated with excessive drug use. DISCUSSION: More than one-third of participants used ≥3 classes of antihypertensive drugs, and it was associated with older age, BMI <25 kg/m2 and FO. Strategies that better manage FO may aid better blood pressure control and avoid the use of multiple antihypertensive medications.

Cyclosporin A tubular effects contribute to nephrotoxicity: role for Ca2+ and Mg2+ ions.

BACKGROUND: Cyclosporin A (CsA) nephrotoxicity has been attributed primarily to renal haemodynamic alterations caused by afferent arteriolar vasoconstriction. However, CsA nephropathy is also characterized by CsA-induced pre-glomerular disturbances and interstitial injury that may occur independently of haemodynamic changes. Given the high lipophilic activity of CsA, we hypothesized that direct tubular injury is likely to contribute to nephrotoxicity. METHODS: To investigate tubular toxicity of CsA, increasing concentrations of CsA (1, 2.5, 10, 25, 50 and 100 micro g/ml) and its vehicle (cremophor) were added to isolated rat proximal tubules (PT). Cell injury was assessed by lactate dehydrogenase (LDH) release. The role of Ca(2+) ions in tubular toxicity and the effect of calcium channel blockers on CsA toxicity were evaluated by measuring intracellular calcium using the fluorescent dye Fura-2 AM. The role of Mg(2+) ions was assessed using high extracellular Mg(2+) medium (2 mM). RESULTS: Whereas cremophor alone was not toxic to PT, CsA caused PT injury but only at the highest concentration (100 micro g/ml). After 90 min incubation, LDH was 22.5% in control PT and 41.9% in PT treated with 100 micro g/ml CsA (P < 0.001, n = 11). There was a transient increase in intracellular calcium ([Ca(2+)](i)) after CsA administration. A low calcium medium (100 nM) prevented CsA injury to renal tubules. However, verapamil, but not nifedipine, enhanced cell damage. Only nifedipine completely prevented [Ca(2+)](i) increases following CsA. Finally, a high Mg(2+) medium attenuated CsA-induced injury. CONCLUSION: We found that high CsA concentrations caused Ca(2+)- and Mg(2+)-dependent PT injury. Thus, low extracellular Ca(2+) and high Mg(2+) media attenuated CsA-induced tubular injury. Verapamil, but not nifedipine, enhanced CsA tubular toxicity. Therefore, CsA-induced tubular injury may contribute to CsA nephrotoxicity independently of haemodynamic disturbances.

Análisis de respuesta dinámica para la represa de río Blanco : Ejemplo de microzonificación lineal

Cuando se tiene una estructura de tierra infinitamente larga, como puede ser un dique o una represa, fundada sobre depósitos de suelo heterogéneos, los efectos de amplificación local pasan a tener especial importancia. En este caso, aún a pesar de que la estructura de tierra pueda resistir la excitación sísmica de diseño, el hecho de que existan zonas localizadas con mayor amplificación, implicaría una concentración de esfuerzos cortantes. Como resultado, podrían producirse deformaciones diferenciales, las cuales pueden no afectar la estabilidad del dique, pero pueden producir grietas transversales de tracción. Este efecto es mucho más perjudicial, pues permite el flujo de agua a través del dique. Este estudio presenta los resultados de una microzonificación lineal (~1.0 Km de longitud) a lo largo del eje de la futura represa de río Blanco, en el área de Naguabo, Puerto Rico. El objetivo ere determinar si existen zonas de mayor amplificación debido a las condiciones geotécnicas locales(AU)

[The safety and efficacy of systemic salvage thrombolysis in acute myocardial infarct]. / Sicurezza ed efficacia della trombolisi di salvataggio per via sistemica nell'infarto miocardico acuto.

BACKGROUND: Thrombolysis reduces mortality in patients with acute myocardial infarction hospitalized within 6 hours of the symptom onset. Infarctions involving a small area of the myocardium show a lower mortality in comparison to those involving a large area. The aim of this study was to evaluate the safety and efficacy of rescue thrombolysis in patients with large acute myocardial infarction who had failed standard thrombolysis. METHODS: From January 1995 to December 1997, ninety patients (69 males, 21 females, mean age 56.7 +/- 9 years), hospitalized for suspected acute myocardial infarction within 4 hours of the symptom onset, suitable for thrombolysis (first episode), and who experienced pain and showed persistent ST segment elevation 120 min after starting thrombolysis, were randomized (single blind) into two groups: Group A (n = 45) received an additional thrombolytic treatment (rt-PA 50 mg), 10 mg as a bolus plus 40 mg in 60 min; Group B (n = 45) received conventional therapy. Positive non-invasive markers were defined as follows: resolution of chest pain; > 50% reduction in ST segment elevation; double marker of creatine phosphokinase (CPK) and CK-MB activity 2 hours after the start of thrombolysis; occurrence of reperfusion arrhythmias within the first 120 min of thrombolytic therapy. Blood pressure, heart rate and ECG were continuously monitored. Echocardiogram was carried out at entry and before discharge to control ejection fraction and segmental wall motion. Adverse events such as death, reinfarction, recurrent angina, incidence of major and minor bleeding, and emergency bypass surgery or coronary angioplasty were checked. RESULTS: Thirty-five patients (77.7%) showed reperfusion (10-50 min) after the start of additional rt-PA. In patients who did not receive additional thrombolysis, only 12 (26.6%) showed reperfusion 65-115 min after the end of rt-PA infusion. Group A showed an earlier and lower CK and CK-MB peak than Group B (p = 0.0001, p = 0.009, and p = 0.002, respectively). Mortality (n = 16, 17.7%) was higher in Group B (n = 13) than in Group A (n = 3) (28.8 vs 6.6%, p = 0.041). Seven patients from Group A showed non-fatal reinfarction. Angina was observed in 18 (40%) patients from Group A and 3 (6.6%) from Group B (p = 0.006). Ten of these patients underwent urgent coronary angioplasty (9 from Group A and 1 from Group B) and 3 from Group A urgent bypass surgery. Minor bleeding was higher in Group A than in Group B (44.4 vs 15.5%, p = 0.047). A major bleeding was observed in Group A (non-fatal stroke). At predischarge echocardiogram ejection fraction was higher in Group A than in Group B (46 +/- 8 vs 38 +/- 7%, p = 0.0001). CONCLUSIONS: Our data suggest that an additional dose of a thrombolytic drug in patients with unsuccessful thrombolysis is feasible, and the bleeding increase is an acceptable risk in comparison with the advantages obtained from a reduced infarct extension. Rescue thrombolysis could save time and allow mechanical revascularization to be carried out in patients admitted to a hospital without interventional cardiology laboratory or in those who have to be refereed to other hospitals for urgent bypass surgery.

Relato de caso: alteraçöes metabólicas como causa de rabdomiólise e insuficiência renal aguda / Relate of case: metabolic alteration a cause of rabdomyolisis and of acute renal failure

A rabdomiólise näo traumática pode ter como causas metabólicas a hiperosmolaridade, a hipofosfatemia e a hipocalemia. É relatado um caso de paciente diabético näo insulino dependente, que desenvolveu coma hiperosmolar, convulsöes, hipofosfatemia, tendo evoluído comrabdomiólise e insuficiência renal aguda näo dialítica. Säo revistos os principais mecanismos fisiopatológicos envolvidos na gênese da rabdomiólise provocada por alteraçöes metabólicas , o tratamento da conseqüente insuficiência renal aguda e a sua prevençäo

Efficacy of rescue thrombolysis in patients with acute myocardial infarction: preliminary findings.

Thrombolysis reduces mortality in patients with acute myocardial infarction (AMI) who are hospitalized within 6 hours from the onset of symptoms. AMIs involving a small area of myocardium show a lower mortality in comparison with AMI involving a large area. The present study was aimed at evaluating the safety and efficacy of rescue thrombolysis in patients with large AMI who had failed thrombolysis. Ninety patients (69 Males and 21 Females), mean age 56.7 +/- 9 years, hospitalized for suspected AMI within 4 hours from the onset of symptoms, suitable for thrombolysis (First episode), and showing pain and persistent ST segment elevation 120 minutes after starting thrombolysis, were randomized (double-blind) into two groups. Group A (45 patients: 10 females and 35 males) received an additional thrombolytic treatment (rTPA 50 mg), 10 mg as bolus plus 40 mg in 60 minutes. Group B (45 patients: 11 females and 34 males) received placebo. Positive noninvasive markers were defined as follows: (1) resolution of chest pain, (2) > or = 50% reduction in ST segment elevation, (3) double marker of creatine kinase (CK) and CK-MB activity 2 hours after the start of thrombolysis, and (4) occurrence of reperfusion arrhythmias within the first 120 minutes of thrombolytic therapy. Blood pressure, heart rate, and ECG were continuously monitored. An echocardiogram was carried out at entry, and before discharge, to control ejection fraction and segmentary kinetics. Adverse events such as death, re-AMI, recurrent angina, incidence of major and minor bleeding, and emergency CABG/PTCA were checked. The groups were similar in terms of age, sex, diabetes, smoking habits, hypertension, and adjuvant therapy (beta-blockers). No significant difference was observed between the two groups regarding the time elapsed from the onset of symptoms to thrombolysis and AMI localization. Thirty-five patients (77.7%) showed reperfusion (10-50 minutes) after commencement of additional rTPA. Of the patients receiving placebo, 12 (26.6%) showed reperfusion within 35-85 minutes. Group A showed an earlier and lower CK and CK-MB peak than the control group, (respectively, p = 0.0001-0.009 and 0.002). Mortality (17.7%, 16 patients) was higher in group B than in the additional rTPA group, i.e., 6.6% (3 patients) in group A versus 28.8% (13 patients) in Group B (p = 0.041). Seven patients from group A showed nonfatal re-AMI. Angina was observed in 18 patients (40%) from group A and 3 (6.6%) from group B (p = 0.006). Ten of these patients underwent urgent PTCA (9 from group A and 1 from group B), and 3 from group A underwent urgent CABG. Minor bleeding was higher in group A than in group B (44.4% versus 15.5%, p = 0.047). Major bleeding was observed in group A (nonfatal stroke). At predischarge, the echocardiogram ejection fraction was higher in group A than in group B (46 +/- 8% versus 38 +/- 7%, p = 0.0001). Our data suggest that an additional dose of thrombolytic drug in patients with unsuccessful thrombolysis is feasible and also that the bleeding increase is an acceptable risk in comparison with the advantages obtained in reducing AMI extension. Rescue thrombolysis can allow a gain in time to perform mechanical revascularization in patients admitted to hospital without an interventionist cardiology laboratory or in those who have to be referred to another hospital for urgent CABG.

[Comparison of the echo-dobutamine-atropine test and ergometric test in the diagnosis of coronary disease]. / Confronto tra test eco-dobutamina-atropina e test ergometrico nella diagnosi di malattia coronarica.

BACKGROUND: A prospective study has been done on 46 patients with suspected coronary artery disease (CAD). They had no history of myocardial infarction (MI) and a normal basal kinetic echocardiography. This was done in order to evaluate the overall accuracy of dobutamine-atropine stress echocardiography (DAS) compare to exercise stress test (ET) for the diagnosis of CAD. METHODS: All the patients after suspension of coronary therapy, performed a casual sequence with both maximal or symptom limited exercise testing (treadmill-Bruce protocol) and DAS. The dobutamine has been given while monitoring systemic blood pressure, electrocardiography and echocardiography in steps of 10 mcg/kg/min' per 3 min' up to a maximum of 40 mcg/kg/min'. Atropine has been added (0.25-1 mg) in patients who did not reach the theoretical maximal cardiac frequency. The test is considered positive when kinetic segmental left ventricular dysfunction appeared. CAD was defined as 50% luminal area stenosis in at least 1 coronary artery at coronary angiography. RESULTS: Significant CAD was present in 27/46 patients (59%). Compared with ET, DAS had significantly higher sensitivity (59% vs 92%, p = 0.01). The different sensibility between the two tests was higher on these patients with a 1 vessel disease (40% vs 86%, p = 0.02). There were no significant differences in specificity among the two tests (79% vs 84%, respectively). Differences in overall accuracy between ET and DAS were significant (67% vs 89%, p = 0.02). CONCLUSIONS: The results of our study show that the DAS is a safe and feasible technique with high sensibility (especially in patients with single CAD) and specificity. This is a valid alternative to the traditional ET, especially for these patients unable to exercise or these who are poorly motivated to achieve a work load sufficient to make the test interpretable.