Liver preservation with HTK: salutary effect of hypothermic aerobiosis by either gaseous oxygen or machine perfusion

The aim of the present study was to improve the viability of marginal livers from non-heart beating donors upon cold preservation using two different techniques for the provision of tissue aerobiosis. Livers from male Wistar rats (250-300 g bw) were harvested after 60 min of cardiac arrest, flushed via the portal vein with 20 mL of heparinized Ringer's solution and 60 mL of histidine-tryptophan-ketoglutarate (HTK) preservation solution. Control livers were then stored submerged in HTK for 24 h at 4 degrees C while other organs were subjected to aerobic conditions by either insufflation of gaseous oxygen via the venous vascular system of the cold stored organ (VSOP) or pulsatile machine perfusion (MP) with oxygenated HTK at 5 mL/min at 4 degrees C. Superoxide dismutase (SOD) (7500 IU) was added to the last 10 mL of HTK in order to prevent adverse effects of high oxygen tensions at hypothermia. Viability of the livers was assessed upon isolated perfusion in vitro with oxygenated Krebs-Henseleit buffer at constant flow. VSOP or MP, both significantly improved vascular conductivity upon reperfusion as evaluated by portal venous pressure, reduced hepatic enzyme release and led to a rise in hepatic bile production upon reperfusion. Induction of apoptosis was also looked for in tissue homogenates by Western analysis for cleavage of poly(ADP-ribose)polymerase (PARP). Expression of cleaved PARP fragment could be found in reperfused control livers but also, though to a lesser extend, after VSOP or MP. In conclusion, provision of oxygen during cold preservation significantly contributes to improve organ viability upon reperfusion and must be regarded as a useful adjunct for marginal or pre-damaged livers. HTK has been shown for the first time to be also suitable for long-term MP preservation of the liver, but, as inferred from these data, simple insufflation of gaseous O2 may be considered a feasible alternative.     

A phase II study of Irofulven (MGI 114) in patients with stage IV melanoma

Sixteen patients with stage IV melanoma,who were heavily pretreated, received11 mg/m²/day of intravenous Irofulvenfor five consecutive days every 28 days.There were no objective tumor responses,although one patient exhibited stabledisease after 4 cycles. The most commontoxicities were grade 1/2 nausea, vomiting,fatigue, anemia, and thrombocytopenia. Onepatient required a dose reduction for anelevated creatinine while another patientrequired cessation of treatment because ofacute ataxia that may have been related toIrofulven. Based upon these data, Irofulvendoes not demonstrate significant antitumoractivity to warrant further investigationin advanced melanoma.     

Cyclosporins: structure-activity relationships for the inhibition of the human FPR1 formylpeptide receptor

The human formylpeptide receptor (FPR) is a seven-transmembranous G-protein-coupled receptor (7TM-GPCR) for chemotactic peptides of bacterial origins, possibly involved in the recruitment and activation of neutrophils in various inflammatory diseases of mucosal epithelia. Mutational analyses suggest that interactions of formylated peptides with FPR occur on the outer exoplasmic leaflet/domains of the plasma membrane. The immunosuppressive and antifungal antibiotic cyclic undecapeptide cyclosporin A (CsA; cyclo-[MeBmt(1)-Abu(2)-MeGly(3)-MeLeu(4)-Val(5)-MeLeu(6)-Ala(7)-D-Ala(8)-MeLeu(9)-MeLeu(10)-MeVal(11)]) and some tested analogues such as [Ala(2)]-CsA, [Thr(2)]-CsA, [Val(2)]-CsA, and [Nva(2)]-CsA were able of inhibiting the binding of formylpeptides to the FPR, with [D-MeVal(11)]-CsA (CsH) being much more active than the other analogues. CsH is devoid of immunosuppressive and antifungal activities, and its large potency for human FPR inhibition is of inverse agonism origin. Formylpeptide binding to FPR-expressing cells does not only induce chemotaxis; it also causes a rapid release of granule enzymes in the extracellular medium, allowing the easy monitoring of any inhibition of FPR function "in vivo" (with intact live cells). With such an assay, CsH was confirmed to be the most potent FPR inhibitory cyclosporin, although a far related immunosuppressive cyclosporin analogue, FR901459 ([Thr(2), Leu(5), Leu(10)]-CsA), was found to display a high FPR inhibitory activity (FPR-InhA). To establish structure-activity relationships (SAR) for FPR function inhibition, 59 cyclosporins were now studied by this standardized assay (with differentiated human leukemic cell line HL-60 as FPR-expressing cells and with N-acetyl-beta-D-glucosaminidase release as read-out). These SAR confirmed the low FPR-InhA of classical cyclosporins, where such activity was only seldom found: the most active ones ([Thr(2), Ile(5)]-CsA, [aMeIle(11)]-CsA, and [MeAla(11)]-CsA) remained 3-10-fold less potent than CsH. In contrast, the SAR disclosed that N(10)-desmethylated cyclosporins were particularly prone to display a large FPR-InhA: their most potent one was a [Thr(2), Gly(3), Leu(5), D-Hiv(8), Leu(10)]-CsA, found to be only 2-4-fold less active than [D-MeVal(11)]-CsA (CsH), with which it shows six differences out of 11 residues. Because the free conformations of both CsH and N(10)-desmethylated cyclosporins differ from those of "classical" (N(10)-methylated, [L-MeVal(11)]-using) cyclosporins, these potent FPR inhibitory cyclosporins probably bind to FPR pharmacophores for which classical cyclosporins show little affinity. Moreover, because the conformations of the N(10)-desmethylated cyclosporins widely differ from the CsH one, they probably bind to different pharmacophores on the FPR molecules.     

Intermittent explosive disorder: epidemiology,diagnosis and management

Intermittent explosive disorder (IED) is characterised by discrete episodes of aggressive impulses that result in serious assaultive acts towards people or destruction of property. IED causes severe impairments in daily function. The diagnosis of IED should be made only after a thorough medical work-up. A structured or semi-structured diagnostic interview is helpful to ensure that comorbid and pre-existing conditions are considered. There is a lack of controlled trials of agents for the treatment of patients with IED, but there is evidence that mood stabilisers, antipsychotics, beta-blockers, alpha(2)-agonists, phenytoin and antidepressants may be useful. Behavioural interventions may be valuable as part of the overall treatment of IED.     

Effects of voice therapy as objectively evaluated by digitized laryngeal stroboscopic imaging

Objective measurements derived from digitized laryngeal stroboscopic images were used to demonstrate changes in vocal fold vibration and in the size of benign lesions after 3 months of voice therapy. Forty chronically dysphonic patients were studied. By means of a rigid stroboscope, pretreatment and posttreatment recordings were made of the vocal folds at rest and under stroboscopic light during phonation. From each recording, images of the positions at rest and during vibration at maximal opening and at maximal closure were digitized. The surface areas of any lesions and of the glottal gap were independently measured in the digitized images by 2 experienced laryngologists. Referential distances were determined in order to compensate for discrepancies in magnification in the various recordings. After 3 months of voice therapy, significant improvement in lesion size and degree of maximal closure during vibration could be demonstrated in about 50% of the patients. The degree of maximal opening did not prove to be a significant parameter.     

Nutrition affects fat-free body composition in broiler chickens

The independence of fat-free body composition from nutrition is assumed in most models that simulate animal growth. This assumption has not been investigated extensively. We studied the allometric relationships between water and ash with protein in growing broiler chickens and tested whether the amounts of water or ash at a given protein weight was affected by nutritional factors. Two experiments, each with a 2 x 9 factorial design, were conducted using male broiler chickens of two body weight ranges [200-800 g (expt. 1) and 800-1600 g (expt. 2)]. The treatment factors were two levels of feed intake and nine dietary ideal protein to protein-free energy ratios (PE-ratio). Protein was balanced for amino acid content. The allometric relationships of water and ash with protein were different for carcass and organs. The relationship between water and protein was not affected by nutrition, except for a 7% reduction in water weight at a fixed protein weight in the carcass in expt. 1 at the lowest compared with the highest PE-ratio (P < 0.001). The relationship between ash and protein was strongly affected by nutrition. The lowest PE-ratio increased ash weight at a fixed protein weight in the carcass by up to 28%, compared with the highest PE-ratio (P < 0.001). We conclude that, at least for modern meat-type animals, nutrition can significantly affect fat-free body composition at a certain fat-free body weight. The nutritional effects on fat-free body composition could be incorporated into models of the chemical body composition of growing animals.     

Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973-1995

The purpose of our study was to examine the incidence patterns of 2 major histologic types of esophageal cancer, in selected countries world-wide and to identify components of birth cohort, period and age as determinants of observed time trends using regression modeling. The roles of temporal changes in specification of histology of tumors and of classification of cancers at the gastroesophageal junction as esophageal or gastric in origin were taken into consideration. In all, 56,426 esophageal cancer cases were included. The results indicate that the incidence rate of squamous cell carcinoma of the esophagus has been relatively stable in most of the countries analyzed, although increasing trends were observed in Denmark and the Netherlands (Eindhoven) among men and in Canada, Scotland and Switzerland among women. There was a significant increase in the incidence of esophageal adenocarcinomas in both sexes in the United States (among whites and blacks), Canada and South Australia and in 6 European countries (Scotland, Denmark, Iceland, Finland, Sweden and Norway). In France the increase was limited to men and in Switzerland the increase was observed only in women. Modeling was unable to distinguish which trends were the results of changes in risk between generations (as cohort effects), or changes in all age groups simultaneously (as a period effect).