Biochemical basis of 5-aminolaevulinic acid-induced protoporphyrin IX accumulation: a study in patients with (pre)malignant lesions of the oesophagus.

Administration of 5-aminolaevulinic acid (ALA) leads to porphyrin accumulation in malignant and premalignant tissues, and ALA is used as a prodrug in photodynamic therapy (PDT). To understand the mechanism of porphyrin accumulation after the administration of ALA and to investigate whether ALA-induced protoporphyrin IX might be a suitable photosensitizer in Barrett's oesophagus and adenocarcinoma, we determined the activities of porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) in various malignant and premalignant as well as in normal tissues of the human oesophagus. A PDT power index for ALA-induced porphyrin accumulation, the ratio of PBG-D to FC normalized for the normal squamous epithelium of the oesophagus, was calculated to evaluate intertissue variation in the ability to accumulate porphyrins. In malignant and premalignant tissue a twofold increased PBG-D activity and a marginally increased FC activity was seen compared with normal squamous epithelium. A significantly increased PDT power index in Barrett's epithelium and adenocarcinoma was found. Our results suggest that, after the administration of ALA, porphyrins will accumulate in a greater amount in Barrett's epithelium and adenocarcinoma of the oesophagus because of an imbalance between PBG-D and FC activities. The PDT power index here defined might be a useful indicative parameter for predicting the susceptibility of these tissues to ALA-PDT

Porphyrin biosynthesis in human Barrett's oesophagus and adenocarcinoma after ingestion of 5-aminolaevulinic acid

5-Aminolaevulinic acid (ALA)-induced porphyrin biosynthesis, which is used for ALA-based photodynamic therapy (ALA-PDT), was studied in tissues of 10 patients with Barrett’s oesophagus (BE) and adenocarcinoma of the oesophagus (AC) undergoing oesophagectomy at a mean time interval of 6.7 h after the ingestion of ALA (60 mg kg–1). In BE, AC, squamous epithelium (SQ) and gastric cardia, the activities of the haem biosynthetic enzymes porphobilinogen deaminase (PBG-D) and ferrochelatase (FC) and the PDT power index – the ratio between PBG-D and FC in BE and AC in comparison with SQ – were determined before ALA ingestion. Following ALA administration, ALA, porphobilinogen, uroporphyrin I and PPIX were determined in tissues and plasma. The PDT power index did not predict the level of intracellular accumulation of PPIX found at 6.7 h. In BE, there was no selectivity of PPIX accumulation compared to SQ, whereas in half of patients with AC selectivity was found. Higher haem biosynthetic enzyme activities (i.e. PBG-D) and lower PPIX precursor concentrations were found in BE and AC compared to SQ. It is therefore possible that PPIX levels will peak at earlier time intervals in BE and AC compared to SQ. © 2000 Cancer Research Campaig

Search for cosmological mu variation from high redshift H2 absorption; a status report

Observations of H2 spectra in the line-of-sight of distant quasars may reveal a variation of the proton-electron mass ratio mu=m_p/m_e at high redshift, typically for z>2. Currently four high-quality systems (Q0347-383, Q0405-443, Q0528-250 and J2123-005) have been analyzed returning a constraint Dmu/mu < 1 x 10^{-5}. We present data and a mu-variation analysis of another system, Q2348-011 at redshift z_{abs}=2.42, delivering dmu/mu = (-1.5 \pm 1.6) x 10^{-5}. In addition to observational data the status of the laboratory measurements is reviewed. The future possibilities of deriving a competitive constraint on Dmu/mu from the known high-redshift H2 absorbers is investigated, resulting in the identification of a number of potentially useful systems for detecting mu-variation.Comment: 13 Pages, 4 Figures, JENAM conference (Lisbon); accepte

Standard values and relationship-specific validity of the Bielefeld Relationship Expectations Questionnaire (BFPE)

<p>Abstract</p> <p>Background</p> <p>The Bielefeld Partnership Expectations Questionnaire (BFPE) is a tool to assess attachment in the romantic relationships of adults. The attachment styles are operationalized as configuration patterns of scale scores. While convergent validity has already been investigated, discriminant validity is still lacking confirmation.</p> <p>Methods</p> <p>The present sample (n = 1509) is representative for the German population aged 18 to 50. The mean age was 34.6 years. Most of the participants lived in a relationship (77.3 %). Discriminant validity was analyzed using a marital quality questionnaire (PFB), a social support questionnaire (F-Soz-U K-14), and a life satisfaction questionnaire (FLZ).</p> <p>Results</p> <p>All the BFPE scales have a satisfying internal consistency between r = .79 and .86. Those individuals who showed a secure pattern, i.e. increased "Readiness for Self-Disclosure" and "Conscious Need for Care" as well as reduced "Fear of Rejection" experienced their partner as socially supportive, reported higher marital quality in all of its facets, and were more satisfied within the life-domains "family/children" and "relationship/sexuality". Standard values for each scale are presented.</p> <p>Conclusions</p> <p>The BFPE has repeatedly been verified as a short, reliable, and valid instrument applicable to research practice with healthy individuals as well as within clinical contexts.</p

Non-linear viscoelastic behavior of abdominal aortic aneurysm thrombus

The objective of this work was to determine the linear and non-linear viscoelastic behavior of abdominal aortic aneurysm thrombus and to study the changes in mechanical properties throughout the thickness of the thrombus. Samples are gathered from thrombi of seven patients. Linear viscoelastic data from oscillatory shear experiments show that the change of properties throughout the thrombus is different for each thrombus. Furthermore the variations found within one thrombus are of the same order of magnitude as the variation between patients. To study the non-linear regime, stress relaxation experiments are performed. To describe the phenomena observed experimentally, a non-linear multimode model is presented. The parameters for this model are obtained by fitting this model successfully to the experiments. The model cannot only describe the average stress response for all thrombus samples but also the highest and lowest stress responses. To determine the influence on the wall stress of the behavior observed the model proposed needs to implemented in the finite element wall stress analysis

Early neoplastic and metastatic mammary tumours of transgenic mice detected by 5-aminolevulinic acid-stimulated protoporphyrin IX accumulation

A photodynamic technique for human breast cancer detection founded upon the ability of tumour cells to rapidly accumulate the fluorescent product protoporphyrin IX (PpIX) has been applied to transgenic mouse models of mammary tumorigenesis. A major goal of this investigation was to determine whether mouse mammary tumours are reliable models of human disease in terms of PpIX accumulation, for future mechanistic and therapeutic studies. The haeme substrate 5-aminolevulinic acid (5-ALA) (200 mg kg−1) was administered to mouse strains that develop mammary tumours of various histological subtypes upon expression of the transgenic oncogenes HRAS, Polyoma Virus middle T antigen, or Simian Virus 40 large T antigen in the mammary gland. Early neoplastic lesions, primary tumours and metastases showed consistent and rapid PpIX accumulation compared to the normal surrounding tissues, as evidenced by red fluorescence (635 nm) when the tumours were directly illuminated with blue light (380–440 nm). Detection of mouse mammary tumours at the stage of ductal carcinoma in situ by red fluorescence emissions suggests that enhanced PpIX synthesis is a good marker for early tumorigenic processes in the mammary gland. We propose the mouse models provide an ideal experimental system for further investigation of the early diagnostic and therapeutic potential of 5-ALA-stimulated PpIX accumulation in human breast cancer patients

Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent

BACKGROUND: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. METHODS: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours

Permanent 125I-seed prostate brachytherapy: early prostate specific antigen value as a predictor of PSA bounce occurrence

<p>Abstract</p> <p>Purpose</p> <p>To evaluate predictive factors for PSA bounce after ¹²⁵I permanent seed prostate brachytherapy and identify criteria that distinguish between benign bounces and biochemical relapses.</p> <p>Materials and methods</p> <p>Men treated with exclusive permanent ¹²⁵I seed brachytherapy from November 1999, with at least a 36 months follow-up were included. Bounce was defined as an increase ≥ 0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Biochemical failure (BF) was defined using the criteria of the Phoenix conference: nadir +2 ng/ml.</p> <p>Results</p> <p>198 men were included. After a median follow-up of 63.9 months, 21 patients experienced a BF, and 35.9% had at least one bounce which occurred after a median period of 17 months after implantation (4-50). Bounce amplitude was 0.6 ng/ml (0.2-5.1), and duration was 13.6 months (4.0-44.9). In 12.5%, bounce magnitude exceeded the threshold defining BF. Age at the time of treatment and high PSA level assessed at 6 weeks were significantly correlated with bounce but not with BF. Bounce patients had a higher BF free survival than the others (100% versus 92%, p = 0,007). In case of PSA increase, PSA doubling time and velocity were not significantly different between bounce and BF patients. Bounces occurred significantly earlier than relapses and than nadir + 0.2 ng/ml in BF patients (17 vs 27.8 months, p < 0.0001).</p> <p>Conclusion</p> <p>High PSA value assessed 6 weeks after brachytherapy and young age were significantly associated to a higher risk of bounces but not to BF. Long delays between brachytherapy and PSA increase are more indicative of BF.</p