The effect of core composition in biodegradable oligomeric micelles as taxane formulations.

Docetaxel (DCTX) and paclitaxel (PTX) are very potent anti-cancer drugs, but the currently marketed formulations, Taxotere and Taxol, respectively, are associated with vehicle-related toxicity. An attractive alternative to formulate these hydrophobic cytotoxic agents are polymeric micelles. In this study, the loading of taxanes into oligomeric micelles composed of mPEG750-b-oligo(epsilon-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group was investigated. Next, the release characteristics and cytotoxicity of the loaded micelles were studied. MPEG750-b-OCL5 -OH micelles loaded with taxanes formed unstable particles with rapid leakage of the drug. In contrast, the presence of an aromatic end group (Bz or Np) resulted in the formation of small (10nm), almost monodisperse micelles with stable encapsulation of 10% (w/w) of PTX or DCTX. This was ascribed to a better compatibility between the micellar core and the drug as compared to the oligomers with the hydroxyl end group. 1H NMR studies showed that the micellar core was liquid, and that PTX was molecularly dissolved in the core. The in vitro stability was studied in PBS at 37 degrees C, which showed that leakage of PTX from 10% and 5% (w/w) loaded mPEG750-b-OCL5-Bz micelles started after 8 and 24h, respectively. The presence of albumin did not affect the stability, suggesting that the micelles are not destabilised and the drug was not extracted from the micellar core by this protein. The in vitro cytotoxic effect of the taxane-loaded micelles on C26 carcinoma cells was comparable to that of the commercial formulations, but the empty micelles were far less toxic than the Cremophor EL vehicle. The results show that mPEG-b-oligo(epsilon-caprolactone) micelles hold good promise for the formulation of taxanes.     

Expression of genes of potential importance in the response to chemotherapy in osteosarcoma patients

BACKGROUND: The prognosis of patients with osteosarcoma has considerably improved over the last 30 years, mainly due to developments in chemotherapy. However, almost half of the osteosarcomas do not respond to chemotherapy. Predictive markers for chemosensitivity at diagnosis are desirable. PATIENTS AND METHODS: In order to investigate the potential of some chemotherapy-associated genes with respect to their predictive value for chemosensitivity, the mRNA expression of 8 genes was evaluated in the osteosarcomas of 45 patients and correlated to the histological response to neoadiuvant chemotherapy. RESULTS: ERCC4, a member of the nucleotide excision repair system, showed a orrelation between expression and the histologically evaluated response to chemotherapy. The expression of the other investigated genes HER-2/neu, HSP 70, GST, DHFR, BCRP, ERCC1 and Mlh1 showed no significant correlation to response to chemotherapy. CONCLUSION: In our retrospective analyses, low expression of ERCC4 was shown to be related to poor response to chemotherapy. The potential value of ERCC4 as response predictor has to be investigated in a prospective study.     

Mycobacterium tuberculosis Beijing genotype

Molecular epidemiologic studies of strains of Mycobacterium tuberculosis are currently conducted worldwide. The genetically distinct Beijing family of strains has been associated with large outbreaks of tuberculosis, increased virulence, and multidrug resistance. However, in this first population-based search for Beijing strains in the Danish DNA fingerprint database, analysis of 97% of all culture-positive tuberculosis patients in 1992 to 2001 showed that 2.5% of 3,844 patients, 1.0% of Danish-born patients, and 3.6% of immigrants (from 85 countries) had Beijing strains. No Beijing strains were found among 201 strains from Danish-born patients sampled in the 1960s, and no evidence of an increase in Beijing strains was found over time. The true prevalence of Beijing strains worldwide is unknown because only a fraction of global strains have been analyzed.     

Reaction to the paper: Interaction of Polysorbate 80 with Erythropoietin: A Case Study in Protein–Surfactant Interactions

Micelle-associated epoetin is still a possible explanation for the upsurge of pure red blood cell aplasia associated with subcutaneous use of epoetin alpha in patients with chronic renal failure.     

Focal cortical dysplasia possibly related to a probable prenatal ischemic injury

Focal cortical dysplasias are a frequent etiology of partial seizure disorders refractory to medical treatment. We report the case of a patient with focal cortical dysplasia, confirmed by surgery, in association with ischemic cerebral lesions that possibly occurred during the intra-uterine development. This observation reinforces the hypothesis of a possible factor of causality between prenatal ischemia and anomalies of cortical development.     

Physical activity and glucose tolerance in elderly men: the Zutphen Elderly study

PURPOSE: To determine whether physical activity is associated with glucose tolerance in the elderly. METHODS: We examined current and 5-yr change in physical activity in relation to glucose tolerance in 424 randomly selected male inhabitants of the Dutch town Zutphen, aged 69-89 yr, without known diabetes mellitus. Physical activity was assessed by a validated questionnaire designed for retired men. Glucose intolerance was assessed by an oral glucose tolerance test and defined as impaired glucose tolerance or diabetes mellitus. RESULTS: Men with 30 min x d(-1) or more of physical activity of at least moderate intensity had a lower prevalence of glucose intolerance as compared to men without these activities (age-adjusted odds ratio 0.32; 95% CI, 0.18-0.57). Adjustment for family history of diabetes, smoking, alcohol intake, dietary factors, body mass index, and subscapular skin-fold thickness or exclusion of men with cardiovascular diseases or disabilities did not substantially change the results. With specific activities modeled simultaneously, bicycling (P for trend = 0.01) and gardening (P for trend = 0.02) were inversely associated with glucose intolerance. Men whose amount of physical activity had decreased during the past 5 yr had significantly higher age-adjusted 2-h glucose concentrations as compared with men who remained at least as active (difference 0.7 mmol x L(-1); 95% CI, 0.1-1.3). CONCLUSION: These findings suggest that common types of physical activity such as bicycling and gardening may contribute to the prevention of glucose intolerance in elderly men     

Clinical validation of a new olfactory test

A new approach to clinical olfactometry is presented using nasal sprays. A special dosage valve was used to standardize an aerosol size to 40 μm. For evaluation a 6 × 6 matrix (substance/olfactory quality) with verbal associative clues was used according to test psychological findings. Validation took place in three steps after determining smell-associated thresholds in preliminary examinations. Recognition of different aromas administered either by spraying into the open mouth from a distance of 5 cm using nasal sprays or sniffing opened bottles was compared in 50 subjectively normosmic subjects. Findings showed that the correspondence between the two procedures was relatively high, with global identification of odorous substances as high as 98.4% in the spray test. The number of substances used was next reduced to those six substances providing the most reproducible results in an investigation with 56 normosmic and 55 hyposmic subjects. Verbal associative clues were also tested. In a last step 50 patients with hyposmia of various origin and 110 normosmic subjects were tested, allowing previous results to be reproduced regardless of the cause of hyposmia. The spray test was shown to be easily performed and was suitable as a screening test, with a sensitivity of 88% and a specificity of 100%. Received: 29 September 1997 / Accepted: 11 February 1998     

Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis

BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.     

Coronary hybrid revascularization from January 1997 to January 2001: a clinical follow-up

Background. Hybrid revascularization (HyR), combining minimally invasive left internal mammary artery (LIMA) bypass grafting to the left anterior descending coronary artery (LAD) and catheter interventional treatment of the remaining coronary lesions, avoids the disadvantages associated with cardiopulmonary bypass (CPB). We investigated the clinical follow-up of 57 patients with multivessel disease undergoing this procedure in the last 4 years.

Methods. Between January 1997 and January 2001, 57 consecutive patients (41 men and 16 women, aged 65.7 ± 7.9 years) with coronary artery disease (two-vessel, n = 34; three-vessel, n = 23) were treated with off-pump LIMA-to-LAD bypass combined with balloon angioplasty and stenting of the remaining significantly obstructed (> 50%) coronary vessels. Clinical follow-up data included a early postoperative and a 6-month control angiography and a patient interview in January 2001.

Results. All patients underwent LIMA-to-LAD bypass-grafting and balloon angioplasty in 72 coronary lesions without procedural-related complications. However, one early LIMA bypass occlusion was documented during coronary angiography. Postoperatively no deterioration of preexistent organ dysfunction was observed in any patient. The mean follow-up was 100.7 ± 37.9 weeks in 55 of 57 patients (97%). Control angiography 6 months after HyR (n = 34) revealed a patent LIMA bypass in 33 patients and 8 in-stent restenoses (> 50%) in the coronary arteries that were treated interventionally by re-PTCA (n = 6) or by conventional CABG (n = 1). In 1 patient medical treatment resulted in significant reduction of angina so no further intervention was considered necessary. After HyR 1 patient died 18 months later of an intracerebral hemorrhage. All other patients are alive and doing well.

Conclusions. Our results indicate that in selected patients with multivessel disease including left main stem stenosis HyR is an effective and secure procedure with excellent early and good midterm results. Especially elderly patients with severe concomitant diseases appear to benefit from this approach by avoiding CPB.