Human cytochrome P450 4F3: structure, functions, and prospects

Cytochrome P450 4F3 (CYP4F3), originally identified as one of the leukotriene B4 ω-hydroxylases, belongs to a CYP gene family that comprises several members, which participate in the metabolism of various endobiotics, as well as some xenobiotics. The CYP4F gene family is clustered in a 0.5-Mb stretch of genomic DNA on the p13 region of chromosome 19. Apart from the ω-hydroxylation of leukotriene B4 and prostaglandins, CYP4F3 is the main catalyst in the oxidation of fatty acid epoxides. CYP4F3 expression results from the synthesis of two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule. Remarkably, the selection of either isoform is part of a tissue-specific control through which CYP3F3A is mostly expressed in leukocytes and CYP4F3B mostly in the liver. Recently, CYP4F3 single nucleotide polymorphisms have been incriminated in the onset of pathologies, including celiac or Crohn's diseases. Although much has been discovered in the regulation and function of CYP4F2, the closest CYP4F subfamily member, analyses of CYP4F3 enzymes lag somewhat behind in the field of our knowledge. In this short review, emphasis will be placed on the regulation and the functional roles of human CYP4F3.     

Vocational support in mental health service delivery in Australia

Background: Individuals experiencing severe and persistent mental illness report a desire to gain and sustain work. Individual Placement and Support (IPS) is an evidence-based approach to vocational rehabilitation to support competitive employment outcomes.

Aim/Objective: This study aimed to evaluate whether a joint-governance management partnership, between a clinical adult mental health and an employment service, could deliver a sustained IPS program in Australia.

Materials and Method: The methodology entailed a Clinical Data Mining approach, to examine records from seven years of implementation of IPS in one setting within an Australian public mental health service context.

Results/Findings: Despite the prevalence of schizophrenia spectrum diagnoses and an older mean age (39 years), indicating that a large proportion of the cohort had experienced serious mental illness for over twenty years, findings were that 46.3% of participants achieved employment.

Conclusions: This is an excellent result and is comparable to the only randomised control trial, with adult services, in the Australian context, which found a 42.5% employment rate possible under IPS compared with just 23.5% with referral to external employment services.

Significance: More extensive trialling of IPS across clinical services is required, in Australia and internationally, including fidelity protocols, for knowledge translation to be achieved.     

Drug injection cessation among HIV-infected injecting drug users

This article reports findings from a cohort study that investigated drug injection cessation over an 18-month period among HIV-infected injecting drug users followed up in a clinical setting. At 18th month visit, individuals reporting persistent injection practices were compared with individuals who reported drug injection cessation for at least 12 months. Crude and adjusted odds ratios were used to assess the impact of change in addictive and sexual behaviors, contacts with the drug network, depression, negative life events, clinical status, HIV therapy, and drug maintenance treatment (DMT) on drug injection cessation. After multiple adjustment, a general decrease of addiction practices (alcohol and cannabis) and of unsafe sexual behaviors significantly accompanied injection cessation. Individuals with higher education level, still in contact with the drug network, and not yet treated for their HIV disease were significantly more likely to persist injecting behaviors. These results underscore the importance and the need of monitoring addiction practices and unsafe sexual behaviors among HIV-positive individuals to properly address primary and secondary prevention in the era of highly active antiretroviral treatments (HAART).     

Athero-express: Differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design

In clinical practice, biological markers are not available to routinely assess the progression of atherosclerotic disease or the development of restenosis following endarterectomy or catheter based interventions. Endarterectomy procedures provide an opportunity to study mechanisms of restenosis and progression of atherosclerotic disease since atherosclerotic tissue is obtained. Athero-Express is an ongoing prospective study, initiated in 2002, with the objective to investigate the etiological value of plaque characteristics for long term outcome. Patients are included who undergo an endarterectomy of the carotid artery. At baseline blood is withdrawn, patients fill in an extensive questionnaire and diagnostic examinations are performed. Atherosclerotic plaques are freshly harvested, immunohistochemically stained and examined for the presence of macrophages, smooth muscle cells, collagen and fat. Parts of the atherosclerotic plaques are freshly frozen to study protease activity and protein and RNA expressions. Patients undergo a duplex follow up to assess procedural restenosis (primary endpoint) at 3 months, 1 year and 2 years. Secondary endpoints encompass major adverse cardiovascular events. In the future, the creation of this biobank with atherosclerotic specimen will allow the design of cross-sectional and follow up studies with the objective to investigate the expression of newly discovered genes and proteins and their interaction with patients and plaque characteristics in the progression of atherosclerotic disease. Objective is to include 1000–1200 patients in 5 years. In January 2004, 289 patients had been included. It is expected that 250 patients will be included yearly.     

Economic consequence of local control with radiotherapy: cost analysis of internal mammary and medial supraclavicular lymph node radiotherapy in breast cancer

PURPOSE: To investigate the financial implications of radiotherapy (RT) to the internal mammary and medial supraclavicular lymph node chain (IM-MS) in postoperative breast cancer. METHODS AND MATERIALS: A cost-effectiveness and cost-utility analysis were performed, using Markov models, comparing the early and delayed costs and effects of IM-MS during a 20-year time span from a societal viewpoint. The outcome estimates were based on Level I evidence from postoperative RT literature and the cost estimates on the standard practice of the Leuven University Hospitals, with the RT costs derived from an activity-based costing program developed in the department. RESULTS: On the basis of the assumptions of the model and seen during a 20-year time span, primary treatment including IM-MS RT results in a cost savings (approximately 10,000) compared with a strategy without RT. Because IM-MS RT also results in better clinical effectiveness and greater quality of life, the treatment with IM-MS dominates the approach without IM-MS. Sensitivity analyses confirmed the robustness of these results in all tested circumstances. Although threshold values were found for the cost of IM-MS, the cost at relapse, and the quality of life after treatment, these were substantially different from the baseline estimates, indicating that it is very unlikely that omitting IM-MS would become superior. CONCLUSION: This ex-ante cost evaluation of IM-MS RT showed that the upfront costs of locoregional RT are easily compensated for by avoiding the costs of treating locoregional and distant relapse at a later stage. The cost-sparing effect of RT should, however, be evaluated for a sufficiently long time span and is most specifically found in tumors with a rather slow natural history and a multitude of available systemic treatments at relapse, such as breast cancer.     

Post-seizures amygdaloallocortical microvascular lesion leading to atrophy and memory impairment

Although the incidence of seizures after a cerebrovascular event including intracerebral hemorrhage has been widely recognized, the present studies have demonstrated that generalized convulsive seizures can cause multifocal amygdaloallocortical hemorrhage and tissue necrosis, the origin of which remains to be established. The seizure-elicited amygdaloallocortical injured area, which we refer to as a focal injury-prone area (FIPA), was caused by cholinergic stimulation of the ventroposterolateral and thalamic reticular nuclei. The amygdaloallocortical injury was preceded by focal absence of neuronal COX-2 and presence of microvascular immunoreactivity to the pro-inflammatory cytokines, IL-1beta and TNF-alpha. The microvascular inflammation was followed by edema and multifocal amygdaloallocortical microhemorrhages, leading to atrophy and cognitive impairment. On the basis of the present results, we conclude that generalized convulsive seizures may be at the origin of amygdaloallocortical microvascular injury suggesting that, in addition to anticonvulsant treatment, an appropriate clinical evaluation and therapy for seizures-associated cerebrovascular accidents should be considered.