Action of n-alkanes on drug-metabolizing enzymes from guinea-pig liver

Treatment of guinea-pig liver microsomal preparations with n-pentane, n-hexane and n-heptane enhanced both p-nitrophenol and o-aminophenol glucuronidation. The apparent K_m values of UDPglucuronate, for both p-nitrophenol and o-aminophenol UDPglucuronyltransferase, and of o-aminophenol were considerably increased, whereas the apparent K_m value of p-nitrophenol was the same after n-pentane treatment. No solubilization of UDPglucuronyltransferase or other microsomal proteins was observed after treatment with the n-alkanes. However, a substantial release of phospholipids from microsomal membranes occurred. The relative capacity of the different alkanes to release phospholipid was the same as the relative activation of UDPglucuronyltransferase. Aniline p-hydroxylation was considerably increased by the alkanes at concentrations of about 15–30 times lower than those necessary for optimal activation of UDPglucuronyltransferase. At these concentrations no activation of the aminopyrine N-demethylation was observed, whereas at higher concentrations a gradual decrease in both N-demethylating and p-hydroxylating activities occurred. n-Heptane, at a concentration which optimally activated aniline p-hydroxylation, markedly increased the rate of NADPH-cytochrome P-450 reduction. This suggests that the increase of the p-hydroxylating rate by n-heptane is related to a reversal of the cytochrome P-450 reduction by aniline.     

The role of surgery in stage IIIA non-small cell lung cancer

For most patients who have stage III non-small cell lung cancer (NSCLC), a combination of chemotherapy and radiation represents the current treatment of choice. Recent developments include the use of adjuvant chemotherapy after up-front surgery in subgroups of patients who have stage III disease, as well as innovative ways to deliver concurrent chemoradiotherapy or combinations of chemotherapy with higher-dose conformal radiotherapy techniques. This article focuses on patients who have stage IIIA NSCLC and reviews the different possibilities for their treatment. Special emphasis is given to the inclusion of surgery into the different approaches to this disease stage. The current literature on this topic is reviewed, and the different aspects of surgical treatment in the management of stage IIIA NSCLC are discussed.     

Blood-brain barrier opening with alkylglycerols: Biodistribution of 1-O-pentylglycerol after intravenous and intracarotid administration in rats

Short-chain alkylglycerols have been described to increase the penetration of drugs and macromolecules across the blood-brain barrier (BBB) into the central nervous system (CNS) and were considered to be of potential value in the pharmaceutical treatment of CNS disorders. Due to the lack of information on the pharmacological behavior of these compounds in vivo, pharmacokinetics and biodistribution of [14C]- and [3H]-labeled 1-O-pentylglycerol (49 mg/kg, 100 mM) was investigated in normal male Wistar rats after intravenous as well as intracarotid administration. There was a rapid and predominant renal elimination of 1-O-pentylglycerol and more than 70% of administered dose was found in the urine within 270 min. Analysis of the pharmacokinetic parameters after a single i.v. bolus injection of 1-O-pentylglycerol resulted in a peak blood concentration of 0.58+/-0.06 micromol/ml, an initial half life of 23+/-7 min and a terminal half life of 18.8+/-4.1 h. No accumulation of 1-O-pentylglycerol was observed in the brain or other organs while highest concentrations were found in liver and thymus. This was confirmed by autoradiographic studies. Five minutes after intracarotid administration, high radioactivity was found in the ipsilateral brain, whereas after 30 min radioactivity in the brain has dramatically decreased. Autoradiographic images gave evidence of biliary excretion in addition to the renal elimination. There were no signs of cleavage of the O-alkyl bond in vivo as demonstrated by HPLC analysis.In conclusion, 1-O-pentylglycerol is characterized by pharmacological properties appearing very favorable for in vivo use as a permeabilizing drug for increased drug delivery to the brain.     

Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients

BACKGROUND: Carcinoma of the paranasal sinuses is rare. Standard therapeutic modalities consist of surgery and radiotherapy (RT). Because of the often advanced stage and the vicinity of optic structures, RT-induced ocular toxicity is a feared side effect of conventional RT. Intensity-modulated radiotherapy (IMRT) is a relatively new technique, which is implemented with the hypothesis that, compared with conventional RT, it would result in a lower rate of ocular toxicity for an equal local control (LC). METHODS: Between 1998 and 2003, 39 consecutive patients received postoperative irradiation by means of IMRT for an adenocarcinoma (n = 31) or squamous cell carcinoma (n = 8) of the paranasal sinuses (n = 36) or nasal cavity (n = 3). T-classification was T2 in 41%, T3 in 15%, T4a in 23%, and T4b in 21% of patients. Invasion through the cribriform plate was seen in 11 patients. Orbital invasion was present in 36% of patients. The median delivered dose was 70 gray (Gy) (range, 60-70 Gy). The authors compared the overall survival (OS) and LC of the patients with a historic cohort (HC) (n = 30), treated with conventional or 3-dimensional conformal RT. RESULTS: The median follow-up was 31 months. The actuarial OS rates were 68% at 2 years and 59% at 4 years. The actuarial LC rates were 73% at 2 years and 68% at 4 years. Invasion through the cribriform plate was a significant prognostic factor for LC and OS, with a median time to local disease recurrence of 7 months if present, and a 2-year LC rate of 90% if not present. In the comparison between the IMRT and HC groups, no significant differences were found for LC and OS. Acute toxicity was mild. Two patients developed decreased vision after RT. No RT-induced blindness was observed. CONCLUSIONS: Postoperative IMRT for sinonasal carcinoma resulted in good LC, with a low acute toxicity and no RT-induced blindness.     

Higher failure rate and stem migration of an uncemented femoral component in patients with femoral head osteonecrosis than in patients with osteoarthrosis

BACKGROUND: Several authors have found poorer outcome after hip replacement for osteonecrosis than after hip replacement for arthrosis. In a retrospective study we evaluated the performance of an uncemented femoral component in patients with osteonecrosis and arthrosis of the hip. PATIENTS AND METHODS: 31 patients operated for osteonecrosis, and 49 patients operated for osteoarthrosis were included. The median follow-up time was 6.1 (2-11) years for the patients with osteonecrosis, and 5.9 (4-8) for the arthrosis patients. RESULTS: Migration analysis performed by the Einzel-Bild-Roentgen Analysis (EBRA) technique revealed a median stem migration of 1.5 (-8.8-0) mm in the patients with osteonecrosis, but only 0.6 (-2.8-0.7) mm in the patients with arthrosis (p < 0.001). Survivorship analysis with stem revision as endpoint for failure was 74% (95% CI: 55-94) in the osteonecrosis, and 98% (95% CI: 94-100) in the arthrosis group (p = 0.01). INTERPRETATION: We suggest that the higher failure rate and stem migration of uncemented total hip replacement in the patients with osteonecrosis is a consequence of the disease. On the basis of these findings, we recommend close monitoring of the patients with osteonecrosis, which should include migration measurements.     

Protection of mice and guinea pigs against tuberculosis induced by immunization with a single Mycobacterium tuberculosis recombinant antigen, MTB41

MTB41 is a Mycobacterium antigen that is recognized by CD4+ T cells early after experimental infection of mice with Mycobacterium tuberculosis and by PBMC from healthy PPD positive individuals. Immunization of mice with plasmid DNA encoding the MTB41 gene sequence results in the development of antigen-specific CD4+ and CD8+ T cells, and protection against challenge with virulent M. tuberculosis. In the present studies, in contrast to DNA immunization, we show, that a strong MTB41-specific CD4+ T cell response, but no MHC class I restricted cytotoxic T lymphocyte (CTL) activity is detected in the spleen cells of infected mice. Therefore, this data suggests that the induction of CD8+ T cell response to MTB41 epitopes by DNA immunization may not be relevant to protection because these epitopes are not recognized during the infectious process. We also compared the repertoire of rMTB41 epitope recognition by CD4+ T cells of M. tuberculosis-infected mice with the recognition repertoire of mice immunized with the recombinant rMTB41 protein. Both regimens of sensitization lead to the recognition of the same molecular epitope. Coincidentally, immunization with the soluble recombinant protein plus adjuvant, a regimen known to generate primarily CD4+ T cells, resulted in induction of protection comparable to BCG in two well-established animal models of tuberculosis (mice and guinea pigs).     

Glycoconjugate histochemistry of the secretory epithelium lining the seminal vesicles of the miniature pig

The present study thoroughly examined the localization and characterization of glycoconjugates in the secretory epithelium lining the seminal vesicles of the miniature pig, employing light and electron microscopic histochemical procedures, including lectin methods. The present results showed the epithelial cells and luminal secretions to contain glycoconjugates with abundant neutral saccharides and a small amount of acidic saccharides, containing varying types of terminal sugar residues. At ultrastructural levels, the free surface coat of the plasma membrane was rich in alpha-D-Man, alpha-D-Glc, beta-D-Gal, GlcNAc, and sialic acid. The flocculent contents of the secretory vesicles indicated the localization of alpha-D-Man, alpha-D-Glc, alpha-L-Fuc, beta-D-Gal, GlcNAc, and sialic acid; such sugar residues were also seen in the elements of the Golgi apparatus. The present results have characterized the seminal vesicles of the miniature pig as having a high secretory activity and copiously producing glycoconjugates with various sugar residues. Such glycoconjugates appear to be indispensable substances for porcine reproduction, possibly influencing the fertilizing capacity of spermatozoa within the female genital tract.     

Transpersonal psychology -- psychology of consciousness: chances and problems

Transpersonal psychology represents a perspective which has gained importance in psychological research and clinical practice over the last years. This paper offers an overview on the history and the sources of transpersonal psychology. Additionally, important themes and topics of transpersonal psychology will be discussed such as a) the importance of spirituality in psychotherapy and counselling, b) spirituality as a resource for maintaining and regaining health, c) spiritual experiences as an avenue to consciousness, d) the delimination of extraordinary states of consciousness and "spiritual crises". In the next paragraph specific problems and critical points of transpersonal psychology are presented. Among them are the discussion of the question whether experience free of language is at all possible as well as the question how notions coming from eastern traditions can be translated into western psychology. Finally, some positive aspects of transpersonal psychology will be presented, and we submit that transpersonal psychology should be taken seriously in a scientific way.     

Retinopathy of prematurity and risk factors: a prospective cohort study

Background  

Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants.