Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer and liver metastasis.

BACKGROUND: EndoTAG-1 (ET), a novel formulation of cationic liposomes carrying embedded paclitaxel (Taxol), shows antitumoral activity, targeting tumor endothelial cells in solid tumors. Patients with advanced metastatic cancer were evaluated investigating effects on pharmacokinetics and tumor vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and contrast-enhanced ultrasound (CEUS). PATIENTS AND METHODS: The pharmacokinetic (PK) profile of ET (22 mg/m(2) i.v.) was evaluated after single and repeated doses. DCE-MRI and CEUS explored hepatic metastases before, during and after the 4-week treatment cycle. Angiogenic biomarkers were assessed. Tumor response was evaluated by modified RECIST. RESULTS: The PK profile demonstrated slight accumulation of paclitaxel after repeated doses. DCE-MRI parameters K(trans) and/or iAUC(60) showed a trend to decrease. Changes of blood flow-dependent parameters of DCE-MRI and CEUS were well correlated. Angiogenic biomarkers revealed no clear trend. ET was generally well tolerated; common toxic effects were fatigue and hypersensitivity reactions. Nine (9 of 18) patients had stable disease after the first treatment cycle. Four patients without disease progression continued treatment. CONCLUSIONS: This study including multiple pretreated patients with different metastatic cancer revealed individually distinctive hemodynamic alterations by DCE-MRI. The PK profiles of ET were similar as observed previously.

[Advances in the diagnostics of Alzheimer's disease]. / Fortschritte in der Diagnostik der Alzheimer-Demenz.

Due to the demographic developments, diagnosis and treatment, dementia constitutes an increasing medical challenge and is likely to have an increasing socioeconomic impact. Dementia does not reflect a single disease but encompasses a variety of underlying conditions, heterogeneous clinical courses and therapeutic approaches, among which Alzheimer's disease represents the most common cause. Therefore, a thorough differential diagnosis of dementia is of major importance. To date the current diagnosis of dementia according to ICD-10/DMS-IV is based on clinical criteria. In addition, the concept of mild cognitive impairment comprises early cognitive dysfunction without clinically apparent dementia. Alzheimer's disease is more and more conceptualized as a disease continuum with mild cognitive impairment as an early and manifest dementia as the later stage of the disease. This review gives an overview on the current diagnostic approaches and the proposed revisions of diagnostic and research criteria for Alzheimer's disease.

Analysis of the open region of RNA polymerase II transcription complexes in the early phase of elongation.

The RNA polymerase II (pol II) transcription complex undergoes a structural transition around registers 20-25, as indicated by ExoIII footprinting analyses. We have employed a highly purified system to prepare pol II complexes stalled at very precise positions during the initial stage of transcript elongation. Using potassium permanganate we analyzed the open region ('transcription bubble') of complexes stalled between registers 15 and 35. We found that from register 15 up to 25 the transcription bubble expands concomitantly with RNA synthesis. At registers 26 and 27 the bubble has a high tendency to retract at the leading edge. Addition of transcription elongation factor TFIIS re-extends the bubble to the stall site, resulting in complexes competent for transcript elongation. These findings are discussed in the light of the recently determined structures for RNA polymerases.

Human telomerase reverse transcriptase antisense treatment downregulates the viability of prostate cancer cells in vitro.

Telomerase, a ribonucleoprotein complex is activated in the vast majority of human malignancies, including prostate cancer. Its inhibition is a putative way to affect cancer proliferation and might be used in the therapy of tumors. We analysed the influence of antisense phosphorothioate oligonucleotides (PTO) against the reverse transcriptase subunit of telomerase on prostate cancer cell viability, telomerase activity and telomere length. DU145 prostate cancer cells were cultivated in PTO containing medium. The PTO-incorporation was confirmed by confocal laser scanning microscopy. Cell viability was measured by a WST-1 tetrazolium assay. After 15 days of antisense PTO treatment, a significant inhibition of cell viability occurred. Telomerase activity was determined by a telomeric repeat amplification protocol (TRAP) assay and telomere length by Southern blot analysis. Since the long-term telomerase antisense treatment reduces the viability of prostate cancer cells significantly, this antisense approach could be a new therapeutic strategy to treat patients with advanced prostate cancer.

Replacement of tunica albuginea of corpus cavernosum penis using human dura. Experimental study on dogs.

The tunica albuginea of corpus cavernosum penis was excised and replaced with human dura in experiments on 11 dogs. The surface of the implant epithelialized within three weeks, and later the implant was replaced by autologous tissue with no scarring and shrinkage. After resection of placques in Peyronie's disease the tunica albuginea can be replaced with specially treated human dura.

Urodynamic effects of oral oxybutynin chloride in children with myelomeningocele and detrusor hyperreflexia.

OBJECTIVES: To investigate the effects of oral oxybutynin chloride (OC) on standard urodynamic measures in children with myelomeningocele (MMC) and detrusor hyperreflexia. METHODS: Forty-one MMC children with detrusor hyperreflexia (19 boys and 22 girls, aged 2 months to 15 years; mean 4.9 years) were evaluated urodynamically before and within 3 months after initiation of oral OC therapy (0.2 to 0.3 mg/kg/day). Therapy with oral OC was always combined with clean intermittent catheterization (CIC). RESULTS: Oral OC treatment caused an increase in bladder capacity from 141 +/- 96 to 197 +/- 99 mL (+ 40%; P < 0.01), a decrease in detrusor pressure at maximal capacity from 45 +/- 32 to 28 +/- 23 cm H2O (-38%; P < 0.01), and an increase in detrusor compliance from 6.5 +/- 5.6 to 16.8 +/- 13.7 mL/cm H2O (+ 158%; P < 0.01). Improvement in urodynamic measures and continence were correlated. After a follow-up of at least 2 years, effective protection of renal function was achieved in 38 of the 41 children (93%) with conservative therapy alone. Adverse effects resulted in discontinuation of oral OC treatment in only 2 cases. CONCLUSIONS: Treatment with oral OC and CIC is effective and safe in children with MMC and detrusor hyperreflexia and should be initiated early when indicated by urodynamic findings.

Automated histomorphometry of interstitial reactions in the heart.

A method is presented suitable to measure changes in area densities of the total Sirius red-stained interstitial tissue in longitudinal sections of rat hearts by means of computer-aided image analysis considering at the same time the behavior of six regions and changes in the percentage of thick connective tissue fibers in the total interstitial tissue. Verification tests were directed to the influences of preparation, adjustment of the grey-level thresholds, and identification of the various regions, to marginal conditions of measurement and the investigators. The reliability of the method with acceptable total errors is demonstrated.

LOH analyses in the region of the putative tumour suppressor gene C13 on chromosome 13q13.

BACKGROUND: In previous studies we isolated a new cDNA fragment named C13 which is down-regulated in malignant prostate tissues. The corresponding gene is localized on chromosome 13q13 between the known tumour suppressor genes (TSG) BRCA-2 and RB-1. MATERIALS AND METHODS: Loss of heterozygosity (LOH) analyses were carried out in the region of C13 in order to investigate the importance of the new putative TSG for prostate cancer development. Using semiquantitative LOH analysis, we screened 21 prostate carcinoma patients of different tumour stages (pT2-pT4) for 14 microsatellite markers in the region of C13 (13q13) and in the flanking BRCA-2 and the RB-1 loci. RESULTS: For 18 (86%) patients LOH or allelic imbalances were found. We identified three to nine alterations in affected tumours per marker. An overall genetic alteration frequency per patient of 38% (86 of 225 informative cases) could be calculated. One important finding regarding the overall frequency of determined microsatellite instability is that the LOH/AI rate of 47% for the seven C13-associated markers was higher than for the four markers of the RB-1 locus (39%) and for the three BRCA-2 markers (25%). Surprisingly, defining LOH critical regions (LCR) for the investigated marker panel, eight of the ten affected LCR cases showed chromosomal imbalances simultaneously for the RB-1 and the C13 LOH markers. CONCLUSIONS: The high LOH rate for eight different microsatellite markers in and around the putative TSG locus C13 on chromosome 13q13 further supports an involvement of C13 in prostate tumourigenesis.

The distribution of the tail moments in single cell gel electrophoresis (comet assay) obeys a chi-square (chi2) not a gaussian distribution.

The parameter tail moment in single cell gel electrophoresis (comet assay) is calculated as the product of the two values: the percentage of DNA in the comet tail and the tail length in microm. Experiments were performed with cultured mammalian cells: B-Lymphoblasts, epithelial cells of a kidney tissue and a plate-epithelial cell line of a human carcinoma. They were irradiated in suspension with UV A at lambda = 343 nm, generated by an excimer laser-pumped dye laser. DNA migration was assessed and analysed. It is demonstrated that the distribution of the tail moments can be fitted by a chi2 (chi-square) distribution, whereas the factors of the product tail moment tend to be normally distributed. From this result, consequences for the statistical evaluation of the results can arise, especially for the computation of the confidence limits and for the valuation of the parameter tail moment from other comet assay experiments.

Coulometric microdetermination of peroxides--I. Hydrogen peroxide.

An electroanalytical method, based on controlled-potential coulometry in the iodine-iodide system, has been developed for determination of small amounts of hydrogen peroxide. The sample is added to an electrolyte containing an acid solution of iodide and the iodine, which is produced rapidly, is reduced at a rotating platinum electrode. The number of coulombs consumed in the cell reaction is determined by electronic integration. Samples containing 1 microg-1 mg of hydrogen peroxide were analysed with an accuracy of +/-0.2%. The analysis time ranged from 3 to 7 min.

Coulometric microdetermination of peroxides-II: organic peroxides.

An iodometric method for the rapid microdetermination of organic peroxides, utilizing electrochemical reduction in the iodine-iodide system, has been developed. After complete reaction between peroxide and iodide in an acidic semi-aqueous medium the iodine produced is reduced at a rotating platinum electrode, at constant potential. Electronic integration is used. Organic peroxides of different reactivities have been analysed by making use of the increased rate of reaction at elevated temperatures. Accurate and precise results were obtained for samples at the 1-mg level and the total time of analysis varied from 8 to 20 min, depending on reactivity.

Ileal conduit urinary diversion 16 months before renal transplantation in a case of non-functioning lower urinary tract.

The case history of a cadaveric kidney graft recipient with complete non-functioning of the lower urinary tract is reported. An ileal conduit was formed 16 months prior to transplantation. The graft ureter was implanted into the conduit without any problems, graft functioning was excellent, and no surgical, metabolic, or infectious complications occurred during the 18-month follow-up period.

[Gene therapy and immunotherapy in prostatic carcinoma]. / Gen- und Immuntherapie beim Prostatakarzinom.

Although local prostate cancer (PC) can be cured in most cases by radical prostatectomy, therapies for metastatic and androgen-independent PC are limited and rather unsatisfactory. Gene and immunotherapy based on progress in molecular biology are novel treatment options especially for these PC stages. In the field of passive immunotherapy, chimeric/recombinant antibodies and derivatives thereof show promising results in early clinical trails (phase I/II). Before treatment, a careful selection of patients who could profit from this therapy is important (theranostics). Concerning active immunotherapy, administration of dendritic cells loaded with PC-specific tumor antigens seems to be an interesting therapy option. Promising gene therapeutic approaches include antisense and suicide gene therapy. Antisense therapy studies revealed the advantage that even systemic treatment does not lead to strong toxic side effects if the target gene is not involved in important cell functions. Improvement of the gene therapy vectors and identification of new therapeutic genes for PC are essential prerequisites for successful application in humans. Present developments of alternative approaches show that future treatments will be very patient specific.

[Experiences with various antireflux operations (author's transl)]. / Erfahrungen mit verschiedenen Antireflux-Operationen.

One hundred and thirty-eight antireflux operations in 94 patients are reported from 1964 to 1974. Bischoff's method was used 44 times with 63% successful results; Lich/Grégoir's method 38 times with 77% success; and Politano/Leadbetter's method 50 times with 92% success. Indications are briefly investigated.

[Results of radical perineal prostatectomy: 14 years' experience (author's transl)]. / Ergebnisse der radikalen perinealen Prostatektomie

One hundred radical perineal prostatectomies are reported, which were performed during the past 14 years. In this series were 36 patients with stage C carcinomas, which could not be operated radically by total prostatectomy. This shows the difficulties in preoperative staging of these tumors. In spite of doing routinely a vesiculography and a lymphography these tumors were frequently undervalued. The 5-year survival rates, being 66.6% in stage A/B and C carcinomas correspond nearly to the results of Belt. The postoperative incontinence rate was 10%. Only two patients retained their potency. There were no postoperative mortalities.

[Comparative statistic of complications in openprostatectomy and transurethral resection (author's transl)]. / Vergleichende Statistik zur Komplikationsrate bei Enukleation und transurethraler Resektion des Prostataadenoms.

On the basis of the case material of 1049 patients, the advantages and disadvantages of enucleation and the transurethral resection of the prostatic adenoma are compared. There are no significant differences in the lethality of the operation. Although at present preference is generally given to the transurethral resection, this procedure appears less favorable to us with regard to the intraoperative complications as well as late complications of urethral strictures, during long-term follow-up.

[Perineal ectopic testis]. / Perineale Hodenektopie.

The case of a 24-year-old patient is presented who was erroneously presumed to have unilateral testicular aplasia following inguinal exploration in early childhood. At the age of 24 years he underwent surgery for a soft perineal mass, which was found to be perineal testicular ectopia associated with a congenital hernia. Histological examination of the excised testicle revealed atrophy of the germinal epithelium. A survey of the literature yielded approximately 175 more cases of perineal testicular ectopia. This is the most frequent from of testicular ectopia with a relative incidence of less than 1% of all cases of undescended testes. Ectopic testes seem only to differ from undescended testes in terms of topography. Little difference can be observed in terms of histology or the incidence of concomitant hernias.

[Epididymal tumors (author's transl)]. / Tumoren des Nebenhodens

Six cases of benign primary epididymal tumor have been investigated in our patients. The tumor size fluctuated between 3 and 35 mm in diameter. Frequency, histology and medical development are described. The majority of epididymal tumors (53%) is comprised of so-called adenomatoid tumors of benign nature and their histogenesis is being discussed. The difficulties of differential diagnosis are pointed out. Since malignity exists in 26% of the cases, the surgical exposure and diagnosis by frozen section is being postulated, when suspicion of epididymal tumor becomes evident.

[Long-term results after kidney transplantation]. / Langzeitergebnisse nach Nierentransplantation.

In this investigation, our own long-term results after kidney transplantation were compared with those in literature, and the influence of recent findings on the survival rate of patients and transplants was analyzed. In 217 kidney transplant patients, the 5 and 9-year-patient survival rate was calculated at 58% and 45% respectively. The 9-year-transplant function rate was 38%. Analogous results can be derived from collective international and European statistics. The long-term patient survival rate after successful transplantation shows better results than comparable statistics of hemodialysis treatment. Analysis of the results fractionated into the years 1970 to 1974, 1975 to 1977 and 1978 to 1981 shows a continuous improvement in the survival rate of patients and transplants. This improvement of results can be attributed to the reduction of surgical complications with increasing experience and particularly to knowledge recently gained in the field of transplantation immunology (compatibility in the HLA-A/B and -DR system, preoperative blood transfusions) and immunosuppression (reduction of steroid doses, supplementary ATG and cyclosporin A medication).