Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

Biochemical and molecular analysis of carboxylesterase-mediated hydrolysis of cocaine and heroin

Background and purpose:

Carboxylesterases (CEs) metabolize a wide range of xenobiotic substrates including heroin, cocaine, meperidine and the anticancer agent CPT-11. In this study, we have purified to homogeneity human liver and intestinal CEs and compared their ability with hydrolyse heroin, cocaine and CPT-11.

Experimental approach:

The hydrolysis of heroin and cocaine by recombinant human CEs was evaluated and the kinetic parameters determined. In addition, microsomal samples prepared from these tissues were subjected to chromatographic separation, and substrate hydrolysis and amounts of different CEs were determined.

Key results:

In contrast to previous reports, cocaine was not hydrolysed by the human liver CE, hCE1 (CES1), either as highly active recombinant protein or as CEs isolated from human liver or intestinal extracts. These results correlated well with computer-assisted molecular modelling studies that suggested that hydrolysis of cocaine by hCE1 (CES1), would be unlikely to occur. However, cocaine, heroin and CPT-11 were all substrates for the intestinal CE, hiCE (CES2), as determined using both the recombinant protein and the tissue fractions. Again, these data were in agreement with the modelling results.

Conclusions and implications:

These results indicate that the human liver CE is unlikely to play a role in the metabolism of cocaine and that hydrolysis of this substrate by this class of enzymes is via the human intestinal protein hiCE (CES2). In addition, because no enzyme inhibition is observed at high cocaine concentrations, potentially this route of hydrolysis is important in individuals who overdose on this agent.     

Oral fungal and bacterial infections in HIV-infected individuals: an overview in Africa

Oral opportunistic infections developing secondary to human immunodeficiency virus (HIV) infection have been reported from the early days of the epidemic and have been classified by both the EC-Clearinghouse and the World Health Organisation (WHO). Among the fungal infections, oral candidiasis, presenting in African HIV-infected patients has been sporadically documented. We review the literature with respect to candidal carriage, oral candidiasis prevalence and the predictive value of oral candidiasis for a diagnosis of underlying HIV disease in African HIV-infected patients. The use of oral candidiasis as a marker of disease progression, the species of yeasts isolated from the oral cavity in Africa and the resistance of the yeasts to antifungal agents and treatment regimens are discussed. Orofacial lesions as manifestations of the systemic mycoses are rarely seen in isolation and few cases are reported in the literature from Africa. In spite of the high incidence of noma, tuberculosis, chronic osteomyelitis and syphilis in Africa, surprisingly there have been very few reported cases of the oral manifestations of these diseases in HIV-positive individuals. Orofacial disease in HIV-infected patients is associated with marked morbidity, which is compounded by malnutrition. The authors indicate specific research areas, initially directed at the most effective management strategies, which would complete data in this important area.     

HIV/AIDS selective infectivity–report of two peculiar cases

We report two peculiar cases that were observed in two communities of Anambra State, South East Nigeria. The first case was a woman of 44 with a history of blood transfusion from a donor of questionable HIV status. A pint of blood was transfused in a private Hospital on the 15 th January, 2000. She has had no form of antiviral therapy until 22nd April, 2008 when she came to the hospital for routine medical check up. Her HIV result came out confirmed positive while that of her husband came out negative. She has had active sexual life with her husband in the previous eight years as they have had some difficulties in getting their desired extra two children having earlier gotten a boy and a girl. The second case involves a family of six. A couple with four children of ages about 6 months, 2 years, 3 years and 5 years. The youngest, a female presented with fever and multiple lymphadenopathy. She tested HIV positive and so was her mother and her second sibling. But her father and two other siblings remained negative at post three and six months intervals from their very first test date with us. These reported cases appear to go contrary to earlier formed opinion on HIV transmission. We support the opinion on a naturally, occurring substance, APOBEC3G which possibly confers permanent immunity against the HIV virus. We recommend clinical trials of the characterized APOBEC3G as a vaccine for non HIV infected persons of all ages and to people living with as a therapeutic drug.     

IL-10 has a protective role in experimental autoimmune uveoretinitis

The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN- gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.      

De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency

Objective  We investigated the application of high-resolution microarray-based comparative genomic hybridisation (array CGH) on a fetus showing increased nuchal translucency (NT).
Design  Case study.
Setting  Tertiary referral obstetrics unit.
Sample  Pregnant woman attended the antenatal clinic.
Methods  Conventional karyotyping and genetic test was carried out for the alpha-globin gene. High-resolution array CGH using the high-density 244K Agilent microarray was performed on fetal blood sample by cordocentesis to investigate the possibility of any genomic imbalance.
Main outcome measures  Detection of chromosomal abnormality.
Results  Karyotyping analysis showed 46,XY. Molecular genetic diagnosis confirms the fetus has Hb-H constant spring disease but cannot explain the increased NT to 3.2 mm. Array CGH analysis discovered a 1.32-Mb microdeletion on chromosome 16p13.11. Deletion at 16p13.11 has been implicated to predispose to autism and/or mental retardation. Baby was delivered at 40 weeks of gestation, and follow up was carried out at 3 months of age without sign of mental retardation/developmental delay.
Conclusions  This case study demonstrated that array CGH can accurately calibrate the size and identify de novo interstitial chromosome imbalances. However, the presence of chromosome copy variants with unknown clinical significance currently limits its wider scale application in prenatal diagnosis and needs further investigations.