In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins

It has been shown recently in China that arsenic trioxide (As2O3) is a very effective treatment for acute promyelocytic leukemia (APL). APL patients resistant to all-trans retinoic acid (ATRA) and conventional chemotherapy can still respond to AS2O3. In this study, we addressed the possible cellular and molecular mechanisms of this treatment by using NB4 cells as a model. The results show that: (1) As2O3 triggers relatively specific NB4 cell apoptosis at micromolar concentration, as proved by morphology, histogramic related nuclear DNA contents, and DNA gel eletrophoresis. (2) As2O3 does not influence bax, bcl-x, c-myc, and p53 gene expression, but downregulates bcl-2 gene expression at both mRNA and protein levels. (3) As2O3 induces a significant modulation of the PML staining pattern in NB4 cells and HL-60 cells. The micropunctates characteristic of PML-RAR alpha in NB4 cells dissappear after treatment with As2O3, whereas a diffuse PML staining occurs in the perinuclear cytoplasmic region. In addition, a low percentage of untreated NB4 cells exhibits an accumulation of PML positive particles in a compartment of cytoplasm. The percentage of these cells can be significantly increased after As2O3 treatment. A similar PML staining pattern is observed in apoptotic cells. (4) ATRA pretreatment does not influence As2O3-induced apoptosis. These results suggest that induction of cell apoptosis can be one of the mechanisms of the therapeutic effect of As2O3. Moreover, this apoptosis induction occurs independently of the retinoid pathway and may be mediated, at least partly, through the modulation of bcl-2, as well as PML-RAR alpha and/ or PML proteins.     

High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy

Patients with Hodgkin's disease (HD) who fail to enter a complete remission after an initial course of combination chemotherapy are usually considered to have an induction failure (IF); this subset of patients has an extremely poor outcome with further conventional therapy. Since 1985, we have entered 30 IF patients into protocols using conditioning with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) followed by autologous stem cell transplantation (ASCT) with bone marrow (19 patients), peripheral blood stem cells (PBSCs; 8 patients), or both (3 patients). All except 2 patients had previously received chemotherapy regimens for HD that contained at least 7 drugs, and 9 had received prior radiotherapy (RT). After documentation of IF, the majority of patients received some cytoreductive therapy as specified by protocol (local RT in 9, two cycles of conventional chemotherapy in 2, both modalities in 2, or high-dose cyclophosphamide to enhance PBSC collection in 11) before CBV +/- P. Five treatment-related deaths occurred, all before day 150 posttransplant. Eleven patients have had progressive HD at a median of 6 months (range, 0.1 to 45 months) after ASCT. The actuarial progression-free survival (PFS) at a median follow- up of 3.6 years (range, 0.2 to 8.2 years) is 42% (95% confidence intervals, 21% to 61%). The statistical analysis identified only prior clinical bleomycin lung toxicity as an adverse risk factor for PFS, mainly because of the increased nonrelapse mortality seen in these patients. CBV +/- P and ASCT can produce durable remission in a substantial proportion of IF HD patients who otherwise have a poor survival, and we believed ASCT approaches represent the best therapy currently available for these patients. Additional measures are needed to reduce the primary problem of disease progression despite high-dose chemotherapy and stem cell transplantation.     

The neurodevelopmental hypothesis of schizophrenia: a review of recent developments

The neurodevelopmental hypothesis (NDH) of schizophrenia suggests that a disruption of brain development during early life underlies the later emergence of psychosis during adulthood. The aim of this review is to chart the challenges and subsequent refinements to this hypothesis, with particular reference to the static versus progressive nature of the putative neurobiological processes underlying the NDH. A non-systematic literature review was undertaken, with an emphasis on major review papers relevant to the NDH. Weaknesses in the explanatory power of the NDH have led to a new generation of more refined hypotheses in recent years. In particular, recent versions of the hypothesis have incorporated evidence from structural neuroimaging which suggests changes in brain volumes after the onset of schizophrenia. More detailed models that incorporate progressive neurobiological processes have replaced early versions of the NDH, which were based on a `static encephalopathy'. In addition, recent models have suggested that two or more `hits' are required over the lifespan rather than only one early-life event. Animal models are providing important insights into the sequelae of disturbed early brain development. The NDH has provided great impetus to the schizophrenia research community. Recent versions of the hypothesis have encouraged more focused and testable hypotheses.     

Eruptive pseudo‐angiomatosis lesions are associated with intravascular neutrophils and do not harbour Epstein–Barr virus

Background Eruptive pseudo‐angiomatosis (EPA) is a rare, relatively newly described cutaneous disorder characterized by the sudden onset of several bright red, angioma‐like papules surrounded by blanched halo. Its aetiology is unknown; however, viral infection or mosquito bites have been speculated as possible causes. Objective This study aims to determine the clinical and histopathological features of EPA, and whether it is associated with Epstein–Barr virus (EBV) infection. Methods We conducted a retrospective chart review of 25 EPA cases from 2006 to 2008. In order to determine latent EBV infection, EBV‐encoded small RNA (EBER) in situ hybridization was performed in 18 subjects. To determine EPA's distinguishing histological characteristics, we compared the cases with 22 control cases of perivascular lymphocytic infiltration for haematoxylin and eosin, CD3, CD4, CD8, CD31 and c‐kit staining patterns. Results The patient sample's female‐to‐male ratio was 2.1 : 1, and the patients’ age ranged from 5 to 79 years (average 46 years). The lesions appeared during the months of July to September in all but 3 patients. Skin biopsies demonstrated capillary ectasia with perivascular mononuclear cellular infiltrates in the upper dermis. Most patients were otherwise healthy, and routine laboratory results were all normal except in one patient who had diabetes. The skin lesions faded without any treatment in 1–2 weeks. Results of EBER in situ hybridization were all negative. The only histological distinguishing feature of EPA was the presence of intravascular neutrophils, which was found to be present in 19 of the 20 EPA cases (95%), in contrast to only 3 of the 22 control subjects (14%) (P < 0.0001). Conclusion The sudden onset of lesions during the summer months among our patients supports the ‘paraviral eruption’ concept of this probably underdiagnosed condition. The significant presence of intravascular neutrophils may be a diagnostic clue of EPA in South Korea.     

Harmful drinking and talking about alcohol in primary care: New Zealand population survey findings

Foulds J, Wells JE, Lacey C, Adamson S, Mulder R. Harmful drinking and talking about alcohol in primary care: New Zealand population survey findings. Objective: Existing evidence suggests low recognition of alcohol problems in primary care. This study aimed to determine the 12‐month prevalence of harmful or hazardous drinking (HHD) in a population sample and to measure the relationship between HHD and talking about alcohol in primary care consultations in that period. Method: A New Zealand population survey of 12 488 adults. Alcohol use in the past 12 months was assessed by the Alcohol Use Disorders Identification Test (AUDIT), with HHD defined as a total score of eight or above. Talking about alcohol was self‐reported. Results: HHD was present in 17.7% and was commoner in men and in younger age groups, with the highest prevalence 53.6% in men aged 18–24. Three per cent of those who attended their usual primary care provider in the past 12 months reported being talked to about alcohol. Talking about alcohol increased with AUDIT score, but was not commoner in young people despite their higher prevalence of HHD. Overall, 9.4% of attendees with HHD reported talking about alcohol. Conclusion: HHD is common but largely not detected in primary care. Improved detection would permit the delivery of effective treatments such as brief interventions.     

A Review of the Cardiometabolic Risk Experience Among Canadian Métis Populations

Cardiometabolic risk is a growing concern in Western society in which rates of cardiovascular disease, diabetes, and obesity are on the rise. Aboriginal populations currently experience unequal burdens of these chronic conditions. However, limited information regarding the experience of cardiometabolic risk among Métis populations is available. This review sought to evaluate the cardiometabolic risk experience among Métis populations in Canada. Canada's Métis population currently experiences greater burdens of chronic conditions including metabolic syndrome, diabetes, obesity, and cardiovascular disease than that of the non-Aboriginal population. Métis populations also experience poorer life expectancy, education, and employment attainments, and reduced access to health care services compared with non-Aboriginal populations. Interventions addressing the deficiencies in sociodemographic, lifestyle, and social determinants among the Métis population might help combat rising experiences of chronic diseases faced by these people. Though the burden of chronic conditions, sociodemographic, lifestyle challenges, and social determinants of health among Métis populations are generally less than that of First Nations populations, Métis people experience these health challenges and influencing factors are generally more similar to that of First Nations than non-Aboriginal peoples. Subsequently, Métis populations need to be included in plans and strategies to reduce chronic conditions among Aboriginal populations. In conclusion, Métis populations experience greater burden of cardiometabolic risk and its components than the general Canadian population.     

What is the optimal serum lithium level in the long-term treatment of bipolar disorder – a review?

Objectives:  There is substantial uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder (BD). This review focuses on the available evidence taking into consideration the effects of previous lithium history, changes in lithium level and polarity of relapse or recurrence.
Methods:  We conducted a MEDLINE search, using the MeSH Terms 'bipolar disorder' and 'lithium' together with 'randomized controlled trial' or 'controlled clinical trial' covering the time span from 1966 to March 2006. We only included studies reporting on the long-term treatment of mood disorders where patients with BD were examined as a separate group and were assigned to precisely specified target ranges of lithium level.
Results:  The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was 0.4 mmol/L with optimal response achieved at serum levels between 0.6–0.75 mmol/L. Lithium levels >0.75 mmol/L may not confer additional protection against overall morbidity but may further improve control of inter-episode manic symptoms. Abrupt reduction of serum levels of more than 0.2 mmol/L was associated with increased risk of relapse.
Conclusions:  In the long-term treatment of bipolar disorder clinicians should initially aim for serum lithium levels of 0.6–0.75 mmol/L, while higher levels may benefit patients with predominantly manic symptoms.