Possible role of CYP2B6 genetic polymorphisms in ifosfamide‐induced encephalopathy: report of three cases

Ifosfamide (IFA) is a potent alkylating antitumoral agent, but its use is limited by neurological side effects. IFA is a racemic mixture of two enantiomeric forms, R‐IFA and S‐IFA with a stereoselective metabolism by CYP3A4 and CYP2B6, leading either to bioactive or to toxic pathways. In three consecutive cases of pediatric patients who exhibited IFA‐induced encephalopathy (IIE), genotyping of clinically relevant single‐nucleotide polymorphisms associated with decreased CYP3A4 and CYP2B6 activities was performed. Genetic investigations revealed the presence of CYP2B6 rs4803419 (C>T) in one patient while the two others carried the CYP2B6*6 allelic variant. All patients carried CYP3A4 wild‐type genotype (CYP3A4*1/*1). Because CYP2B6‐deficient alleles may be responsible for an increased conversion of S‐IFA into neurotoxic metabolites, screening for CYP2B6 polymorphisms may help to avoid IIE and improve clinical outcomes.     

Absence of p53 mutation at codon 249 in duck hepatocellular carcinomas from the high incidence area of Qidong (China)

Dietary aflatoxin and hepatitis B virus infection may play arole in generating the p53 tumor suppressor gene codon 249 hotspotmutation found in human hepatocellular carcinomas (HCCs) fromQidong (China) and southern Africa. No data are available onthe HCC site-specific mutation of the p53 gene in hepadnavirus-infectedanimals exposed to AFB₁. We have searched for the presence ofp53 gene codon 249 mutations in both duck hepatitis B virus(DHBV) positive and negative HCCs of domestic ducks from Qidong,where the human p53 hotspot is so prevalent, as well as in duckHCCs experimentally induced by AFB₁. Direct sequencing of DNAamplification products encompassing p53 codon 249 did not revealany mutations in 11 HCCs from Qidongducks, regardless of thestatus of DHBV infection. In addition no mutation was detectedin four HCCs from AFB₁-treated ducks. This contrasts with thehuman data; however, in humans, the mutation and the preferentialbinding of AFB₁ to codon 249 occurs at the third nucleotideG, while in duck, the codon 249 lacks this G residue. The DNAsequence of adjacent codons is also different in the two specieseven though the amino acid sequence is identical. This may explainthe low frequency of mutation we have observed. In addition,species differences in metabolism and DNA repair could influencethe occurrence of codon 249 mutations.     

Characteristics of guinea-pig immune sera elicited by a synthetic diphtheria toxin oligopeptide

Several oligopeptides of different lengths contained within the Cys 186 Cys 201 first disulfide loop of the diphtheria toxin molecule have been synthesized by a solid-phase method. ¹²⁵I-labeled rabbit antibodies raised against diphtheria toxin reacted specifically with oligopeptides linked to m-nitrobenzhydrylamine resin when the amino acid chain length was equal to or greater than 10 resídues. The synthetic tetradecapeptide (STDP) corresponding to the sequence Gly 188-Cys 201 was used to immunize guinea-pigs. The immune sera obtained reacted with the whole diphtheria toxin molecule as judged by an antigen-linked immunosorbent assay. Anti-STDP sera exhibited a clear, albeit limited, neutralizing effect against the lethal action of diphtheria toxin on cultivated Vero cells. The anti-STDP sera were also able to partially block the ADP-ribosylation of elongation factor 2 mediated by whole diphtheria toxin. In contrast. anti-STDP sera were almost inactive on the enzymic activities of either toxin fragment A or crm 45, a mutant protein which lacks the 15.000 mol. wt C-terminal sequence of the toxin molecule. On the basis of the results obtained, a possible localization of the Cys 188-Cys 201 loop region on the toxin molecule is proposed.     

Homicide et schizophrénie : à propos de 14 cas de schizophrénie issus d’une série de 210 dossiers d’expertises psychiatriques pénales pour homicide

A few murders, which received saturated media coverage, obviously raises questions about the dangerous and violent nature of the mentally-ill, which can sometimes culminate in homicide. Firmly rooted in the collective consciousness is the popular idea that someone who kills an unknown person in the street is mentally-ill. On the contrary, the epidemiological data are reassuring; only 5% of such murders are committed by the persons suffered of schizophrenia.

Aim

To establish the social, clinical and forensic differences between murderers suffering of schizophrenia disorder and murderers who are immune of psychiatric disorder, and especially to compare their respective records of psychiatrics disorder and their respective relationship with their victims.

Method

We studied the cases of 210 murderers, the offences related to the murders, and the social and clinical information collected from psychiatric court reports on persons convicted of homicide. Firstly, we identified the sociodemographic, clinical and criminological profiles of a group of 210 murderers from which were distinguished the schizophrenia murderers. Then, we compared the profiles of murderers suffering from schizophrenia (n = 14), with 73 persons without any mental disorder.

Results

The profile of schizophrenic murderers of our series is characterized by a specific socioprofessional status (single, without child and jobless) and by more frequent records of psychiatrist troubles (this characteristic is always found with criminals that are schizophrenics) and violence against human beings than murderers’ immune of mental disorder. With the exception of these variables and of the clinic of schizophrenia, there is no noticeable difference of sociodemographic profile between schizophrenic murderers and murderers without psychiatric troubles. In addition to the similarities, between the two groups of murderers, in the temporal, location and operating characteristics of the commitment of the homicide (in the evening, at the house of the victim, with three classical means (firearms, knife and knocks), having drunk alcohol), schizophrenic murderers generally commit, alone, a non-premeditated murder. They often strangle their victim in a sudden attack, whereas murderers without a known pathology often premeditate their crime. Therefore, it is possible to talk about a state of emotional violence. In 86% of cases, a delirious psychopathology was at the root of the homicide act of the schizophrenic person. Four criminological themes predominate: persecution, syndrome of influence, mysticism and megalomania. Among the victims of schizophrenic murderers, closest persons to and acquaintance of the murderers are over-represented; in 25% of cases the murder takes place within the family. Finally, penal irresponsibility or mitigation of penal responsibility of the schizophrenic murderer was generally recognized.

Conclusion

Differences between murderers affected with and unaffected with schizophrenia lie on the psychopathology of the morbid process which underlies the homicide of the mentally-ill person.