Nifurtimox biotransformation to reactive metabolites or nitrite in liver subcellular fractions and model systems

Administration of acetaminophen (ACP, 400 mg/kg, i.p.) to fasted, male Swiss-Webster mice caused a rapid 90% decrease in total hepatic glutathione (GSH) and a 58% decrease in mitochondrial GSH by 2 h post ACP. This was followed by a time-dependent decrease (72%) in hepatic AdoMet synthetase activity and rise in plasma ALT levels (>10000 U/l) at 24 h post ACP treatment. AdoMet synthetase activity was maintained at 82, 78 and 60% of controls, respectively, by the cysteine prodrugs PTCA, CySSME and NAC. Total hepatic and mitochondrial GSH levels were also protected from severe ACP-induced depletion by CySSME and MTCA. These results suggest that the maintenance of GSH homeostasis by cysteine prodrugs can protect mouse hepatic AdoMet synthetase, a sulfhydryl enzyme whose integrity is dependent on GSH, as well as the liver itself from the consequences of oxidative stress elicited by toxic metabolites of xenobiotics.     

Are "routine" clinical and laboratory examinations of any help in the treatment of chronic hemodialysis patients?

The relevance of routine physical examinations, laboratory tests, and x-rays in guiding therapeutic decisions was investigated in 54 patients on hemodialysis. Patients were observed for 1 year, while recording all therapeutic interventions and tracing the procedures that had determined them. In no case did a variation in treatment follow the routine physical examination of a patient who was not symptomatic or already signaled for BP or dialytic problems by the hemodialysis nurses. A number of major therapeutic interventions were conversely necessary for acute illnesses that could not be foreseen during the routine physician-patient encounter. Of the many laboratory tests, only the determination of complete blood cell count, serum electrolytes, and calcium and phosphorus levels were frequently associated with therapeutic decisions. No intervention was directly related with x-ray bone examination. On the whole, a subgroup of 11 "high-risk" patients who required frequent and multiple therapeutic interventions was identified, the remaining 43 needing only rare and minor adjustments. It is concluded that routine physical examinations are probably useless in identifying and treating intercurrent problems of patients with chronic end-stage renal failure and that only very few hematochemical laboratory tests should be regularly performed. On the basis of a benefit/risk and benefit/cost examination, it is suggested that personally tailored follow-up schemes would probably be a more appropriate way of monitoring patients on maintenance hemodialysis.     

Transcatheter CT arteriography-guided irreversible electroporation of locally advanced pancreatic adenocarcinoma: A pictorial essay

Visibility of the tumour and its surroundings during the ablative procedure is crucial for optimal treatment planning, needle placement, ablation zone coverage and postprocedural control. The use of transcatheter CT arteriography providing real-time image guidance has proven to be of additional value for thermal liver ablation. The general advantages of the technique could be of value for other indications and ablation techniques as well, especially when requiring multiple needle placements in the vicinity of precarious vascular structures. This pictorial essay presents six clinical cases that illustrate transcatheter CT arteriography guidance during the treatment of locally advanced pancreatic cancer with irreversible electroporation. The illustrations highlight the technique's ability to improve visibility of vascular structures and the advantage of real-time monitoring and treatment of intraprocedural vascular complications. The use of transcatheter CT arteriography can support the interventionalist with respect to periprocedural safety and accuracy of electrode placement for pancreatic irreversible electroporation.     

Co-ordinate regulation of the cystic fibrosis and multidrug resistance genes in cystic fibrosis knockout mice

The cystic fibrosis (Cftr and multidrug resistance (Mdr1) genes encode structurally similar proteins which are members of the ABC transporter superfamily. These genes exhibit complementary patterns of expression in vivo, suggesting that the regulation of their expression may be co- ordinated. We have tested this hypothesis in vivo by examining Cftr and Mdr1 expression in cystic fibrosis knockout transgenic mice (Cftr(tm1CAM)). Cftr mRNA expression in Cftr(tm1CAM)/Cftr(tm1CAM) mice was 4-fold reduced in the intestine, as compared with littermate wild- type mice. All other Cftr(tm1CAM)/Cftr(tm1CAM) mouse tissues examined showed similar reductions in Cftr expression. In contrast, we observed a 4-fold increase in Mdr1 mRNA expression in the intestines of neonatal and 3- to 4-week-old Cftr(tm1CAM)/Cftr(tm1CAM) mice, as compared with age-matched +/+ mice, and an intermediate level of Mdr1 mRNA in heterozygous Cftr(tm1CAM) mice. In 10-week-old, Cftr(tm1CAM)/Cftr(tm1CAM) mice and in contrast to the younger mice, Mdr1 mRNA expression was reduced, by 3-fold. The expression of two control genes, Pgk-1 and Mdr2, was similar in all genotypes, suggesting that the changes in Mdr1 mRNA levels observed in the Cftr(tm1CAM)/Cftr(tm1CAM) mice are specific to the loss of Cftr expression and/or function. These data provide further evidence supporting the hypothesis that the regulation Cftr and Mdr1 expression is co-ordinated in vivo, and that this co-ordinate regulation is influenced by temporal factors.      

Heterozygous and homozygous factor H deficiency states in a Dutch family

Factor H, a 150-kD protein, is an important down-regulating protein of the alternative pathway of the complement system. Presently, only 15 persons, representing seven families, have been described with homozygous factor H deficiency. Deficiency of this protein, inherited as an autosomal recessive trait and resulting in uncontrolled breakdown of C3, results in depletion of components of the alternative pathway (factor B, properdin) and of the terminal pathway (C5), and is associated with the onset of bacterial infections, glomerulonephritis and systemic lupus erythematosus (SLE). The proband of the family in this study suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis due to serogroup X. She had a complete factor H deficiency at the protein level as determined by Western blotting. Among 21 relatives of the proband studied, encompassing three generations, 10 had low factor H levels, including the two children of the proband, indicating a heterozygous factor H deficiency state. In serum samples of the proband and 11 relatives prospectively studied, a strong correlation of factor H levels with C3, C3 haemolytic activity, factor B and properdin levels (P<0.0001) was found. Alternative pathway protein levels were significantly lower (Mann–Whitney test; Z values 3.6–2.7) in sera from the four heterozygous relatives studied than in sera from the seven non-deficient relatives. In addition, a defect of the 37/42-kD H-related protein was found in the proband and two of 21 relatives, compared with four of 40 controls. A defect of the 24/29-kD H-related protein was present in one of 21 relatives studied and in none of the 40 controls.