Role of Bcl-xL in paracetamol-induced tubular epithelial cell death

BACKGROUND: Paracetamol overdose causes acute renal failure and chronic exposure to paracetamol has been linked to chronic renal failure. Recently, apoptosis induction has been identified as a possible mechanism of paracetamol nephrotoxicity. METHODS: Murine proximal tubular epithelial MCT cells were cultured in the presence of paracetamol. The effects of Bcl-xL overexpression, Bax antisense oligodeoxynucleotides, and different caspase inhibitors on cell death were studied. RESULTS: While paracetamol did not change the mRNA expression of the antiapoptotic gene bcl-xL, it decreased Bcl-xL protein levels. The decrease in Bcl-xL was prevented by lactacystin, but not by caspase inhibitors. Addition to the culture media of the survival factors present in fetal calf serum (FCS) increased Bcl-xL expression and decreased paracetamol-induced apoptosis. Overexpression of a human bcl-xL transgene decreased apoptosis induced by paracetamol by 60% at 24 hours and increased long-term cell survival. The constitutive expression of the viral caspase inhibitor CrmA decreased the rate of apoptosis by 60% at 24 hours and the broad-specific caspase inhibitor zVAD-fmk prevented paracetamol-induced features of apoptosis. However, caspase inhibitors did not prevent eventual cell death. Bax did not translocate to mitochondria and Bax antisense oligodeoxynucleotides were not protective. CONCLUSION: Our results suggest that induction of apoptosis may underlie the nephrotoxic potential of paracetamol and identify Bcl-xL as a player in toxic tubular cell injury.     

Modern morpho-functional concepts in cephalic arterial distribution

The present paper provides a general morphofunctional study of the oro-maxillary-facial cephalic arterial area that shows some particular hemodynamic characteristics. The internal maxillary artery supplies a very large territory, with numerous and wide anastomoses. In order to understand the hemodynamic characteristics of this artery, we analyzed some older theories, such as: Ludwig von Bertalanffy's General Systems Theory, Walter Zimmermann's Telome Theory, and some general rheological principles also.     

Paracetamol-induced renal tubular injury: a role for ER stress

Paracetamol (also known as acetaminophen) causes acute and chronic renal failure. While the mechanisms leading to hepatic injury have been extensively studied, the molecular mechanisms of paracetamol-induced nephrotoxicity are poorly defined. Paracetamol induced cell death with features of apoptosis in murine proximal tubular epithelial cells. While paracetamol increased the expression of the death receptor Fas on the cell surface, the Fas pathway was not involved in the paracetamol-induced apoptosis of tubular cells. The mitochondrial pathway was not activated during paracetamol-induced apoptosis; there was no dissipation of mitochondrial potential or release of apoptogenic factors such as cytochrome c or Smac/DIABLO. However, paracetamol-induced apoptosis is a caspase-dependent process that involves activation of caspase-9 and caspase-3 in the absence of cytosolic cytochrome c or Smac/DIABLO. The authors also detected induction of endoplasmic reticulum (ER) stress, characterized by GADD153 upregulation and translocation to the nucleus, as well as caspase-12 cleavage. Interestingly, after treatment of murine tubular cells with paracetamol and calpain inhibitors, the caspase-12 cleavage product was still detectable, and calpain inhibitors were unable to protect tubular cells from paracetamol-induced apoptosis. The results suggest that induction of apoptosis may underlie the nephrotoxic potential of paracetamol and identify ER stress as a therapeutic target in nephrotoxicity.     

Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human vascular cells

Rheumatoid arthritis (RA) is associated with a reduced life expectancy considered to be partly caused by cardiovascular events. A growing concern is that accelerated atherosclerosis is driven by inflammatory mechanisms similar to those responsible for RA. Therefore, selective COX-2 inhibitors, which are widely used for the symptomatic treatment of pain and inflammation in RA, may have an impact on atherosclerotic processes. Their anti-inflammatory properties might provoke anti-atherogenic effects but on the other hand, selective inhibition of anti-thrombotic prostacyclin and COX-2 independent effects might promote the risk of increased prothrombotic activity. In the current study, the effects of the presently marketed selective COX-2 inhibitors celecoxib and rofecoxib on vascular cells have been investigated. Celecoxib inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. At high concentrations, it induced apoptosis and the modulation of inhibitory cell cycle proteins. In contrast rofecoxib-even at high concentrations-had no effect on cell proliferation, apoptosis or cell cycle distribution indicating that celecoxib and rofecoxib do not affect the same signal transduction pathways in endothelial cells. Both drugs did not affect apoptosis induction or cell cycle proliferation in human vascular smooth muscle cells. The observed effects on endothelial cells appear to be COX-independent since both drugs selectively inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for inhibition of prostacyclin production. Regarding endothelial apoptosis as a relevant event in the initiation and progression of atherosclerosis the present data put forward the hypothesis that the presently marketed COX-2 inhibitors have a different impact on atherosclerotic processes.     

Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT?

PURPOSE: To identify the anatomic structures whose damage or malfunction cause late dysphagia and aspiration after intensive chemotherapy and radiotherapy (RT) for head-and-neck cancer, and to explore whether they can be spared by intensity-modulated RT (IMRT) without compromising target RT. METHODS AND MATERIALS: A total of 26 patients receiving RT concurrent with gemcitabine, a regimen associated with a high rate of late dysphagia and aspiration, underwent prospective evaluation of swallowing with videofluoroscopy (VF), direct endoscopy, and CT. To assess whether the VF abnormalities were regimen specific, they were compared with the VF findings of 6 patients presenting with dysphagia after RT concurrent with high-dose intra-arterial cisplatin. The anatomic structures whose malfunction was likely to cause each of the VF abnormalities common to both regimens were determined by literature review. Pre- and posttherapy CT scans were reviewed for evidence of posttherapy damage to each of these structures, and those demonstrating posttherapy changes were deemed dysphagia/aspiration-related structures (DARS). Standard three-dimensional (3D) RT, standard IMRT (stIMRT), and dysphagia-optimized IMRT (doIMRT) plans in which sparing of the DARS was included in the optimization cost function, were produced for each of 20 consecutive patients with advanced head-and-neck cancer. RESULTS: The posttherapy VF abnormalities common to both regimens included weakness of the posterior motion of the base of tongue, prolonged pharyngeal transit time, lack of coordination between the swallowing phases, reduced elevation of the larynx, and reduced laryngeal closure and epiglottic inversion, contributing to a high rate of aspiration. The anatomic structures whose malfunction was the likely cause of each of these abnormalities, and that also demonstrated anatomic changes after RT concurrent with gemcitabine doses associated with dysphagia and aspiration, were the pharyngeal constrictor muscles (median thickness near midline 2.5 mm before therapy vs. 7 mm after therapy; p = 0.001), the supraglottic larynx (median thickness, 2 mm before therapy vs. 4 mm after therapy; p < 0.001), and, similarly, the glottic larynx. The constrictors and the glottic and supraglottic larynx were, therefore, deemed the DARS. The lowest maximal dose delivered to a stricture volume was 50 Gy. Reducing the volumes of the DARS receiving > or =50 Gy (V(50)) was, therefore, a planning and evaluation goal. Compared with the 3D plans, stIMRT reduced the V(50) of the pharyngeal constrictors by 10% on average (range, 0-36%, p < 0.001), and doIMRT reduced these volumes further, by an additional 10% on average (range, 0-38%; p <0.001). The V(50) of the larynx (glottic + supraglottic) was reduced marginally by stIMRT compared with 3D (by 7% on average, range, 0-56%; p = 0.054), and doIMRT reduced these volumes by an additional 11%, on average (range, 0-41%; p = 0.002). doIMRT reduced laryngeal V(50) compared with 3D, by 18% on average (range 0-61%; p = 0.001). Certain target delineation rules facilitated sparing of the DARS by IMRT. The maximal DARS doses were not reduced by IMRT because of their partial overlap with the targets. stIMRT and doIMRT did not differ in target doses, parotid gland mean dose, spinal cord, or nonspecified tissue maximal dose. CONCLUSIONS: The structures whose damage may cause dysphagia and aspiration after intensive chemotherapy and RT are the pharyngeal constrictors and the glottic and supraglottic larynx. Compared with 3D-RT, moderate sparing of these structures was achieved by stIMRT, and an additional benefit, whose extent varied among the patients, was gained by doIMRT, without compromising target doses. Clinical validation is required to determine whether the dosimetric gains are translated into clinical ones.     

The cortical organization of audio-visual sentence comprehension: an fMRI study at 4 Tesla

Neuroimaging studies of written and spoken sentence processing report greater left hemisphere than right hemisphere activation. However, a large majority of our experience with language is face-to-face interaction, which is much richer in information. The current study examines the neural organization of audio-visual (AV) sentence processing using functional magnetic resonance imaging (fMRI) at 4 Tesla. Participants viewed the face and upper body of a speaker via a video screen while listening to her produce, in alternating blocks, English sentences and sentences composed of pronounceable non-words. Audio-visual sentence processing was associated with activation in the left hemisphere in Broca's area, dorsolateral prefrontal cortex, the superior precentral sulcus, anterior and middle portions of the lateral sulcus, middle superior portions of the temporal sulcus, supramarginal gyrus and angular gyrus. Further, AV sentence processing elicited activation in the right anterior and middle lateral sulcus. Between-hemisphere analyses revealed a left hemisphere dominant pattern of activation. The findings support the hypothesis that the left hemisphere may be biased to process language independently of the modality through which it is perceived. These results are discussed in the context of previous neuroimaging results using American Sign Language (ASL).     

The effect of early treatment in children with chronic hepatitis

BACKGROUND: The aim of this study was to compare the efficacy of interferon alpha (IFN) or IFN and ribavirin (IFN+RIB) combination therapy in children with chronic hepatitis C (CHC). Most children were infected during treatment for pediatric malignancies. PATIENTS AND METHODS: We reviewed the charts of 20 patients (11 boys and 9 girls) aged 10.6 +/- 3.7 years with CHC who were treated between 1995 and 2001. Seven patients diagnosed with CHC before 1998 were treated with 3 million units of IFN three times weekly for 6 to 12 months. Thirteen children diagnosed after 1998 were treated with 3 million units of IFN three times weekly plus 15 mg/kg of ribavirin daily for 6 months (IFN+RIB). RESULTS: Demographic and clinical characteristics were not different between the two treatment groups. A sustained complete response defined as serum alanine aminotransferase normalization and hepatitis C virus RNA clearance at 6 and 12 months after termination of treatment occurred in three of seven children (43%) treated with IFN monotherapy compared with 7 of 12 children (54%) in the group treated with IFN+RIB combination therapy (not significant). The only difference between responders and nonresponders was the duration of infection before the initiation of therapy, which was significantly shorter in responders (1 +/- 0.3 vs. 5.6 +/- 2.2; P = 0.001). CONCLUSIONS: In this small cohort of children with CHC, early initiation of antiviral treatment was associated with a sustained response rate independent of treatment type. Regular follow-up of children at risk of acquiring hepatitis C virus infection should assist in the early diagnosis. Early initiation of antiviral treatment may improve the rate of sustained response.     

Long-term results of olfaction rehabilitation using the nasal airflow-inducing ("polite yawning") maneuver after total laryngectomy

OBJECTIVES: To study the long-term results of the nasal airflow-inducing maneuver (NAIM) as an olfaction rehabilitation tool after laryngectomy and to investigate the effectiveness of a new, simpler odor detection test (ODT) called the smell disk test (SDT), or Zürcher Geruchstest. DESIGN: Intervention study. SETTINGS: National cancer center. PATIENTS: Forty-one laryngectomees who received olfaction rehabilitation training with the NAIM 4 months to 2 years earlier. This so-called polite yawning maneuver creates an "underpressure" in the oral cavity, which, in turn, generates a nasal airflow that enables odor molecules to again reach the olfactory epithelium. MAIN OUTCOME MEASURES: Olfaction acuity testing with a standard ODT, along with a questionnaire, providing a subjective olfaction score (present odor perception scale [POPS]), and the SDT, as well as assessment of the patients' correct execution of the NAIM by speech-language pathologists on video recordings made during odor testing and long-term assessment of olfaction acuity. RESULTS: The correlation between the previously used ODT-POPS combination and the SDT was kappa = 0.56 (P<.001). Based on these results, we preferred to use the much simpler SDT instead of the laborious combination of the ODT-POPS. Based on the SDT results, 19 (46%) of the 41 laryngectomees were "smellers" and could be considered normosmic. There was a significant relationship (P =.03) between the patient's correct execution of the NAIM and whether or not the laryngectomee was a smeller according to the SDT. CONCLUSIONS: The effectiveness of the NAIM, or so-called polite yawning technique, for the rehabilitation of olfaction in individuals who have undergone total laryngectomy was reconfirmed. Long-term olfaction rehabilitation was achieved in about 50% of the patients, but more intensified training may be needed to increase the percentage of successfully rehabilitated individuals. The SDT is an effective and simple test for the assessment of olfaction acuity after laryngectomy.