Epstein-Barr virus-associated acute interstitial nephritis: infection or immunologic phenomenon?

Epstein-Barr virus (EBV) DNA in renal tissue in acute interstitial nephritis (IN) has not been previously reported. An 18-year-old male presented with a sore throat, fever, cervical lymphadenopathy, and oliguric renal failure. The rapid slide test for heterophile antibodies associated with infectious mononucleosis was positive, and a renal biopsy showed an acute interstitial nephritis. A polymerase chain reaction (PCR) assay identified EBV DNA in the renal biopsy. In situ hybridization (ISH) for EBV RNA and immunohistochemistry for latent membrane protein 1 of EBV were negative. Hemodialysis and prednisone 60 mg PO OD were administered and the s-creatinine dropped from 1,224 to 75 micromol/l over 9 days. The identification of EBV DNA in the kidney raises the possibility that direct infection plays a role in acute IN associated with EBV.     

Computed tomography – a possible aid in the diagnosis of smoke inhalation injury?

Inhalation injury is an important contributor to morbidity and mortality in burn victims and can trigger acute lung injury and acute respiratory distress syndrome (ARDS) (1-3). Early diagnosis and treatment of inhalation injury are important, but a major problem in planning treatment and evaluating the prognosis has been the lack of consensus about diagnostic criteria (4). Chest radiographs on admission are often non-specific (5, 6), but indicators include indoor fires, facial burns, bronchoscopic findings of soot in the airways, and detection of carbon monoxide or cyanide in the blood (7). Changes in the lungs may be detected by bronchoscopy with biopsy, xenon imaging, or measurement of pulmonary extracellular fluid (4, 5, 8). These methods have, however, been associated with low sensitivity and specificity, as exemplified by the 50% predictive value in the study of Masanes et al. (8). Computed tomographs (CTs) are better than normal chest radiographs in the detection of other pulmonary lesions such as pulmonary contusion (9, 10). The importance of CT scans in patients with ARDS has been reviewed recently (9), but unfortunately there has been no experience of CT in patients with smoke inhalation injury. To our knowledge, there are only two animal studies reporting that smoke inhalation injury can be detected by CT (4, 11); specific changes in human CT scans have not yet been described. Therefore, confronted with a patient with severe respiratory failure after a burn who from the history and physical examination showed the classic risk factors for inhalation injury, we decided to request a CT.     

Involvement of progesterone receptors in ascorbic acid–mediated protection against ischemia-reperfusion–induced acute kidney injury

Background

Ascorbic acid (AA) is an established antioxidant and has been used for treatment of various disorders. Recent reports suggest that administration of AA increases the level of steroids such as progesterone in the body. The present study investigated the protective role of progesterone against ischemia-reperfusion–induced acute kidney injury (AKI) and possible involvement of progesterone receptors in AA-mediated renoprotection in rats.

Materials and methods

The male rats were subjected to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. The rats were treated with progesterone (5 and 10 mg/kg, intraperitoneally) and AA (500 mg/kg, intraperitoneally for 1, 2, and 5 d) before AKI. In separate groups, mifepristone, the progesterone receptor antagonist was administered to rats before progesterone (10 mg/kg) and AA treatment (5 d). Various parameters including creatinine clearance, serum urea, uric acid, potassium level, fractional excretion of sodium, lactate dehydrogenase, and microproteinuria were used to assess kidney injury. Moreover, renal tissues were subjected to quantification of oxidative stress and evaluation of histopathologic changes.

Results

The exogenous administration of progesterone afforded protection against AKI in a dose-dependent manner that was abolished by mifepristone. The administration of AA for 1, 2, and 5 d induced significant increase in serum progesterone levels and afforded protection against AKI. The antioxidant and renoprotective effect of AA was abolished by prior treatment with mifepristone.

Conclusions

It is concluded that exogenous administration of progesterone exerts significant antioxidant and renoprotective effect. Moreover, the progesterone receptors find their explicit involvement in AA-mediated renoprotection against ischemia-reperfusion–induced AKI in rats.     

A 10 min “no‐touch” time – is it enough in DCD? A DCD Animal Study

Donation after cardiac death (DCD) is under investigation because of the lack of human donor organs. Required times of cardiac arrest vary between 75s and 27min until the declaration of the patients' death worldwide. The aim of this study was to investigate brain death in pigs after different times of cardiac arrest with subsequent cardiopulmonary resuscitation (CPR) as a DCD paradigm. DCD was simulated in 20 pigs after direct electrical induction of ventricular fibrillation. The "no-touch" time varied from 2min up to 10min; then 30min of CPR were performed. Brain death was determined by established clinical and electrophysiological criteria. In all animals with cardiac arrest of at least 6min, a persistent loss of brainstem reflexes and no reappearance of bioelectric brain activity occurred. Reappearance of EEG activity was found until 4.5min of cardiac arrest and subsequent CPR. Brainstem reflexes were detectable until 5min of cardiac arrest and subsequent CPR. According to our experiments, the suggestion of 10min of cardiac arrest being equivalent to brain death exceeds the minimum time after which clinical and electrophysiological criteria of brain death are fulfilled. Therefore shorter "no-touch" times might be ethically acceptable to reduce warm ischemia time.     

Inflammatory mechanisms of ventilator‐induced lung injury: a time to stop and think?

Ventilator‐induced lung injury (VILI) is the phenomenon by which mechanical ventilation exacerbates lung injury in critically ill patients. It is particularly relevant for those suffering from acute respiratory distress syndrome, in which the iatrogenic injury caused by VILI contributes to their high mortality. The innate immune system is widely accepted to play an important role during VILI. However, it is our belief that the identification of inflammatory mediators that are crucial during VILI, and thus may make useful therapeutic targets, has become obscured by the wide variety of pre‐clinical animal models of VILI reported in the literature. We aim here to summarise some of our work addressing this issue over the last 10 years, and thus, we hope, make interpretation of a convoluted field a little clearer.     

Apoptotic impact of α1‐blockers on prostate cancer growth: A myth or an inviting reality?

BACKGROUND: Pharmacological manipulation or genetic targeting of the major apoptosis regulators, such as bcl-2, caspases, and inhibitors of apoptosis (IAPs), represent clinically attractive avenues towards effective therapeutic strategies for advanced prostate cancer. A wealth of evidence established the alpha(1)-adrenoceptor antagonists to be clinically effective in relieving the symptoms associated with benign prostatic hyperplasia (BPH) by relaxing prostatic smooth muscle tone. This action alone however does not fully account for the long-term clinical response to these drugs in BPH patients. METHODS: Experimental and retrospective clinical studies provided new evidence supporting a differential growth-suppressing function of two alpha(1)-adrenoceptor antagonists against prostate cancer, independent of an alpha(1)-adrenoceptor mechanism. RESULTS: The quinazoline-based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells. Tamsulosin, a sulphonamide-based, clinically effective alpha(1)-adrenoceptor antagonist for BPH treatment, fails to exert a similar apoptotic action against prostate cells. Furthermore, at pharmacologically relevant doses, doxazosin suppresses benign and malignant prostate growth in in vivo experimental models. The effect is characterized by three intriguing features: (a) it is mediated by an alpha(1)-adrenoceptor-independent action, (possibly related to the quinazoline nucleus); (b) it is targeted at the apoptotic process without affecting cell proliferation; and (c) the elevated apoptotic index correlated with symptom score improvement in BPH patients. CONCLUSIONS: This evidence challenges conventional knowledge of the mechanism of action of alpha(1)-adrenoceptor antagonists, and points to a new therapeutic value for these drugs by providing a differential molecular basis for their anti-tumor efficacy. The present review focuses on the characterization of the apoptotic/anti-angiogenic effect of quinazoline-based alpha(1)-adrenoceptor antagonists against prostate cancer cells and discusses the clinical significance of this action in the prevention and treatment of prostate cancer.