Cytochrome P450 CYP1A1 accumulates in the cytosol of kidney and brain and is activated by heme

Cytochrome P450 CYP1A1 is expressed in most tissues. In brain and kidney, its function remains unclear because its enzymatic activity is barely measurable. Here, we report on the localization of CYP1A1 in the cytosol of kidney and brain, as revealed by immunoblotting with anti-CYP1A1 antibodies and by 7-ethoxyresorufin deethylation (EROD). Hematin (8 microM) added in vitro to cytosol increased the EROD-activity 10-fold in brain olfactory bulb and 7-fold in kidney, presumably by reconstitution of apocytochrome. Succinylacetone, an inhibitor of heme biosynthesis, increased the ratio of cytosolic to microsomal EROD activity of transiently expressed CYP1A1 in COS-1 cells from 1:1 to nearly 6:1. This indicates a strong decrease of microsomal activity with increasing succinylacetone concentration. CYP1A1 activities correlated with CYP1A1 protein assessed by immunoblotting. We conclude that the availability of heme is a limiting factor of P450 function in extrahepatic tissue. Our data further suggest that reduced availability of heme limits the incorporation of P450s into brain endoplasmic reticulum. These observations are important when assessing the function of P450s in extrahepatic tissue.     

Scale-up of polymerization processes

Scale-up and/or scale-down procedures are crucial during the development of chemical processes. These procedures should be integrated to form a multidisciplinary approach encompassing several branches of science and engineering. The challenge is to find a balance between chemistry, design, environment, hygiene and safety (EHS) compliance and economic factors. The iterative process of scale-up procedures also requires concept discrimination at early stages of process development. Scale-up studies should predict the reactor behavior and the quality and properties of a product from laboratory and pilot plant to full scale; however, not every pilot scale presents a valid industrial scaled-down size. A rational mathematical model describing the process reasonably well for large scale is important for designing industrial processing units, but this is only feasible if a phenomenological understanding is achieved, and if the necessary constants and parameters are estimated accurately. An accomplished process development procedure must lead to products presenting the same properties at both small and large scale.     

Globulixanthones A and B,two new cytotoxic xanthones with isoprenoid groups from the root bark of Symphonia globulifera

Bioassay-guided fractionation of a root bark extract of Symphonia globulifera has yielded, in addition to stigmasterol, two new xanthones with isoprenoid units, named globulixanthones A (1) and B (2). The structures of these compounds have been elucidated by spectroscopic means. They possess significant cytotoxicity in vitro against the KB cell line.     

Myocardial angiogenesis resulting in functional communications with the left cavity induced by intramyocardial high-frequency ablation: histomorphology of immediate and long-term effects in pigs

A previous study in rabbit hearts demonstrated the feasibility of creating transmyocardial channels by application of temperature-regulated high-frequency (HF) energy. Feasibility of creating non-transmural channels using a transvascular approach was tested in 14 pigs which were followed for 1 h, and 3 and 9 weeks (group A, B and C). Myocardial channels were found to be highly reproducible and patent in more than two thirds in group A. Channels were replaced by connective tissue during follow-up which contained newly formed small vessels. A functional communication between the left ventricular cavum and newly formed vessels of the channel remnants could be demonstrated in one heart of group C. Thus, intramyocardial HF ablation can be performed with high reproducibility to induce local angiogenesis.     

Side effects of retroviral gene transfer into hematopoietic stem cells

Recent conceptual and technical improvements have resulted in clinically meaningful levels of gene transfer into repopulating hematopoietic stem cells. At the same time, evidence is accumulating that gene therapy may induce several kinds of unexpected side effects, based on preclinical and clinical data. To assess the therapeutic potential of genetic interventions in hematopoietic cells, it will be important to derive a classification of side effects, to obtain insights into their underlying mechanisms, and to use rigorous statistical approaches in comparing data. We here review side effects related to target cell manipulation; vector production; transgene insertion and expression; selection procedures for transgenic cells; and immune surveillance. We also address some inherent differences between hematopoiesis in the most commonly used animal model, the laboratory mouse, and in humans. It is our intention to emphasize the need for a critical and hypothesis-driven analysis of "transgene toxicology," in order to improve safety, efficiency, and prognosis for the yet small but expanding group of patients that could benefit from gene therapy.     

Neurologic complications of anthrax: a review of the literature

A review of the literature suggests that the major neurologic symptom complex of infection by Bacillus anthracis is a fulminant and rapidly fatal hemorrhagic meningoencephalitis and that the reported initial mode of entry can be via the cutaneous or inhalation route. For febrile patients with acute neurologic deterioration with associated findings of dark necrotic pustules on the extremities, gram-positive rods in the cerebrospinal fluid, and multifocal areas of unexplained intracerebral hemorrhage on computed tomographic scans, anthrax should be considered within the differential diagnosis. A low cerebrospinal fluid glucose level has been reported, with gram-positive rods often noted on the gram stain of the cerebrospinal fluid in severely affected patients. Reports indicate that death usually occurs within a week.     

The structure of affective symptoms in a sample of young adults

Symptoms of bipolar disorders include depression and mania. The term "bipolar" implies states that are opposite to each other. Construing scales that define mania and depression as opposite ends of one dimension cannot account for the existence of mixed symptoms. One self-report instrument, the Internal State Scale (ISS), combines both dimensions in one measure. However, the ISS only assesses internal subjective states and does not tap other typical and more objective symptoms of (hypo-) mania. To explore the factorial structure of affective symptoms in a general population sample, we extended the Center for Epidemiologic Studies-Depression Scale (CES-D), adding items to assess manic symptoms as described in DSM-IV. The scale was completed by 2,059 young adults. The results for the original CES-D are comparable to prior studies. Factor-analysis for the extended CES-D revealed two factors in women and men: most manic symptoms loaded high on a factor "euphoria-activation," whereas the other factor included all typical dysphoric-depressive symptoms, but also included the "manic symptoms" of distractibility and irritability. Our results support a two-factor model of bipolar symptoms in the general population with irritability being more closely associated with dysphoria than euphoria. The implications and limitations of the present results are discussed.