Recovery of Renal Function in Heart Transplantation Patients After Conversion From a Calcineurin Inhibitor-Based Therapy to Sirolimus

Background

Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation.

Methods

The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 ± 12.3 years and time since transplantation 8.7 ± 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 ± 0.9 to 1.69 ± 0.5 mg/dL, P = .01) and CrCl (24.9 ± 6.5 to 45.7 ± 17.2 mL/min, P = .005) at 6 months follow-up.

Conclusion

The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.     

Low-high season variation in Plasmodium falciparum erythrocyte binding antigen 175 (eba-175) allelic forms in malaria endemic area of Burkina Faso

Objective  To assess the impact of seasonal variation on the distribution of the eba- 175 allelic forms in the area where malaria transmission is markedly seasonal.
Methods  Blood samples were collected from 291 and 239 children under 5 years of age during the low and the high malaria transmission season, respectively, in four villages named Dawelgué, Kounda, Tanghin and Watenga of Saponé Health District, then screened for eba 175 F- and C- alleles by nested PCR analysis.
Results  F- alleles were more prevalent than C-alleles in the low [0.66 vs. 0.34 ( P  < 0.0001)] and high transmission season [0.67 vs. 0.33 ( P  < 0.0001)]. No significant seasonal variation was observed in the distribution of the two alleles. However, according to Sewall Wright rules, the population pairwise F _ST values, between Dawelgué and Tanghin during the low transmission season ( F _{ST_} value = 0.10415, P -value = 0.0090 and during the high season ( F _{ST_} value = 0.08244, P -value < 0.00001), between Tanghin and Watenga during the low season ( F _ST value = 0.07414, P -value = 0.009) indicated a moderate but statistically significant genetic differentiation.
Conclusion  Although there was a moderate but significant genetic differentiation between some study villages at different times of the year, this study result in the seasonal stability of eba- 175 allele's distribution in the study area.     

Differential modulation of aryl hydrocarbon receptor regulated enzymes by arsenite in the kidney, lung, and heart of C57BL/6 mice

During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR-regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) on the AhR-regulated genes using C57Bl/6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tissues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD-mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In conclusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD-induced AhR-regulated genes in a time-, tissue-, and AhR-regulated enzyme-specific manner.     

Chylous ascites secondary to hyperlipidemic pancreatitis with normal serum amylase and lipase

A 54-year old man with a family history of hyperlipidemia was admitted with a 12 h history of severe generalized abdominal pain associated with nausea, vomiting and abdominal distension. Examination of the abdomen revealed tenderness in the periumblical area with shifting dullness. Serum pancreatic amylase was 29 IU/L and lipase 44 IU/L, triglyceride 36.28 mmol/L. Ultrasound showed ascites. CT of the abdomen with contrast showed inflammatory changes surrounding the pancreas consistent with acute pancreatitis. Ultrasound （US） guided abdomen paracentesis yielded a milky fluid with high triglyceride content consistent with chylous ascites. The patient was kept fasting and intravenous fluid hydration was provided. Meperidine was administered for pain relief. On the following days the patient＇s condition improved and he was gradually restarted on a low-fat diet, and fat lowering agent （gemfibrozil） was begun, 600 mg twice a day. On d 14, abdomen US was repeated and showed fluid free peritoneal cavity. The patient was discharged after 18 d of hospitalization with 600 mg gemfibrozil twice a day. At the time of discharge, the fasting triglyceride was 4.2 mmol/L. After four weeks the patient was seen in the clinic, he was well.     

Decitabine--bedside to bench

PURPOSE OF THE REVIEW: Epigenetic changes marked by DNA methylation are known to contribute to the malignant transformation of cells by silencing critical genes. Decitabine inhibits DNA methyltransferase and has shown therapeutic effects in patients with hematologic malignancies. However, the connection between the clinical activity of decitabine and its demethylating activity is not clear. Herein, we summarize the results of recent clinical trials of decitabine in hematologic malignancies, and review the translational research into decitabine's mechanism of clinical activity. RECENT FINDINGS: Low-dose decitabine has been studied recently in multiple clinical trials and has been shown to be effective for treatment of myelodysplastic syndromes. Correlative laboratory studies of clinical trials have shown that decitabine induces global hypomethylation as well as hypomethylation of gene-specific promoters and activation of gene expression. Past a given threshold, induction of higher degrees of hypomethylation is not directly associated with a better clinical outcome. Moreover, studies have suggested that patients with promoter hypermethylation of p15(INK4B) at baseline have paradoxically a lower chance of achieving response than those without hypermethylation. Furthermore, several other genes activated by decitabine were independent of hypomethylation in the promoter regions. CONCLUSION: While at least part of decitabine's activity is through induction of hypomethylation and reactivation of critical genes, mechanisms independent from hypomethylation are also important for decitabine's antitumor activity.