Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

Metabolic profile modifications in milk after enrofloxacin administration studied by liquid chromatography coupled with high resolution mass spectrometry.

High resolution accurate mass spectrometry (HRMS) operating in full scan MS mode was used in the search and identification of metabolites in raw milk from cows medicated with enrofloxacin. Data consisting of m/z features were taken throughout the entire chromatogram of milk samples from medicated animals and were compared with blank samples. Twenty six different compounds were identified. Some of them were attributed to structures related to enrofloxacin while others were dipeptides or tripeptides. Additionally, enrofloxacin was administered in a controlled treatment for three days. Milk was collected daily from the first day of treatment and until four days after in the search for the identified compounds. The obtained data were chemometrically treated by Principal Component Analysis. Samples were classified by this method into three different groups corresponding to days 1-2, day 3 and days 4-7 considering the different concentration profile evolution of metabolites during the days studied. Tentative metabolic pathways were designed to rationalize the presence of the newly identified compounds.

Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer.

PURPOSE: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7). RESULTS: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53. CONCLUSIONS: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.

Monolithic silica columns with covalently attached octaproline chiral selector. Dependence of performance on derivatization degree and comparison with a bead-based analogue.

A monolithic silica gel chromatographic matrix was derivatized repetitively with an octaproline-derived chiral selector (CS). The increasingly derivatized column was tested after each derivatization reaction. The enantioseparation ability, resolution and efficiency were found to depend on the content of CS attained after each reaction. Moreover, enantioselectivity and performance of the column with the highest CS coverage were compared to those of a bead-based chiral stationary phase (CSP) counterpart. The octaproline-derivatized monolithic column demonstrated increased enantioseparation factors, resolution and broader applicability than the particle-based column. Finally, the loading capacity of the CSPs was also examined. The monolithic octaproline-derived column permits the separation of 3-20 times higher molar amounts of the tested analytes (depending on the compound considered) than the particle-based counterpart. The enhanced capabilities of the derivatized monolithic column with respect to that of a bead-based counterpart cannot be explained only on the basis of an increased CS coverage. The involvement of an effect produced by the chromatographic silica support structure in the obtained results is discussed.

Significance of immunohistochemical c-erbB-2 product localization pattern for prognosis of primary human breast cancer.

Concerning immunohistochemistry of the c-erbB-2 receptor in human mammary carcinoma, membranous immunostaining of tumor cells has been generally considered as a potential risk factor for early recurrence, whereas cytoplasmic reactivity has been neglected. An archival study on 463 patients with primary breast cancers demonstrates that cytoplasmic localization of p185 is significantly correlated with high estrogen and progesterone receptor levels, low histological grade and a low proliferating tumor cell fraction. In accordance with these data, patients bearing mammary carcinomas with cytoplasmic localization of p185 reactivity have a significant better overall survival than those with membranous immunostaining.

Prognostic value of proliferating cell nuclear antigen and c-erbB-2 compared with conventional histopathological factors in breast cancer.

Expression of proliferating cell nuclear antigen (PCNA) and c-erbB-2 oncoprotein has been assessed in 471 women with breast cancer to evaluate their prognostic value as compared to conventional histopathological factors. In univariate analysis, high PCNA expression (> or = 20%) predicted a significantly worse survival in lymph-node-negative tumors (univariate P = 0.031). However, the effect disappeared in multivariate analysis and the histological grade remained the only independent factor for this group. Despite its close correlation to histological grade (P < 0.001), PCNA expression discriminated subsets with different survival within the heterogeneous group of moderately differentiated tumors (univariate P = 0.073, multivariate P = 0.075). PCNA expression was not found to be a significant prognostic factor in lymph-node-positive tumors, thus it was of limited value for breast cancer patients as a whole. c-erbB-2 protein overexpression was associated with a worse survival (univariate P = 0.019, multivariate P = 0.057) for the entire group of patients. The effect was mainly attributed to the significance of c-erbB-2 as an independent factor in lymph-node-positive (up to three nodes, multivariate P = 0.04; four or more nodes: multivariate P = 0.017) and large tumors (> 2 cm: multivariate P = 0.002). c-erbB-2 was without significance in lymph-node-negative patients. Though both factors might amplify the prognostic information for distinct patient subsets they do not achieve the strong prognostic value of conventional histopathological features in breast cancer.

Bonded cellulose-derived high-performance liquid chromatography chiral stationary phases. II. Influence of the porosity of the silica gel matrix on performance.

Two cellulose derivatives bearing simultaneously 10-undecenoyl and 3,5-dimethylphenylaminocarbonyl groups in different ratios were chemically bonded on allylsilica gels of different porosity. The systematic study of the effect of the silica gel pore size on the bonding of the polysaccharide derivative and on the performance of the resulting chiral supports is presented.

Bonded cellulose-derived high-performance liquid chromatography chiral stationary phases. I. Influence of the degree of fixation on selectivity.

Four mixed 10-undecenoyl-3,5-dimethylphenylaminocarbonyl derivatives of cellulose, with an increasing proportion of alkenoyl groups, were synthesized and chemically bonded on allylsilica gel. The influence of the degree of fixation of the cellulose derivative on the matrix for the four resulting chiral stationary phases on their selectivity is discussed.

Covalently bonded polysaccharide derivatives as chiral stationary phases in high-performance liquid chromatography.

Polysaccharide derivatives have been extensively used as chromatographic chiral selectors in chiral stationary phases (CSPs) for the separation of enantiomers by HPLC. When coated onto a silica matrix, they represent nowadays one of the most popular type of CSPs. However, they are only compatible with a limited choice of solvents. The main drawback of these CSPs is related to the solubility of the chiral selector in a number of solvents, which limits their applicability. The different attempts which have been described up to now to overcome this problem by covalently fixing the chiral selector to a matrix are reviewed in this paper.

Mammary serum antigen (MSA), Ca 549, CA 15-3 and CEA in breast cancer preoperative sensitivity and correlation to prognostic factors.

Previously a higher preoperative sensitivity of the mucin like glycoprotein Mammary Serum Antigen (MSA) compared to established tumor markers was reported. The aim of our study was the comparison of MSA and CA 549, CA 15-3 and CEA in primary breast cancer and the correlation to prognostic factors. In 119 patients MSA and CA 549 serum levels were analysed by ELISA, CEA and CA 15-3 levels by LIA. We received the following sensitivities: 30.2% for MSA (cut off = 55 U/mL), 21.8% for CA 549 (cut off = 12.6 U/mL), 20.5% for CA 15-3 (cut off = 25 U/ml) and 10.7% for CEA (cut off = 6 ng/ml). Significant correlations were found between MSA concentrations and grading (p = 0.006), tumor size (p = 0.005) and metastases (p = 0.03). No correlations were found to tumor type, hormone receptors, lymph node status and cathepsin D. MSA is a valuable tumor marker with the highest preoperative sensitivity. Further studies on the value of MSA in the follow-up are necessary.

Preparation of mixed 10-undecenoyl/phenylaminocarbonyl or benzoyl derivatives of chitosan.

The preparation of mixed 10-undecenoyl/phenylaminocarbonyl or benzoyl derivatives of chitosan is described. Several mixed derivatives were prepared using differently substituted aryl isocyanates or benzoyl chlorides. The reactivity of the starting polysaccharide was found to be influenced by the acetyl content.

Characterization of doubly substituted polysaccharide derivatives.

Derivatives of cellulose, amylose and chitosan, bearing simultaneously 10-undecenoyl and arylaminocarbonyl or benzoyl groups were characterized by the combined use of 1H NMR and elemental analysis. The mathematical manipulation of elemental analysis data permits the calculation of the degree of substitution for each kind of substituent. The method was validated and is applicable to other derivatives.

[Can the high-resolution 13-MHz ultrasonography facilitate the preoperative localization and marking of microcalcification clusters?]. / Kann die hochauflösende 13-MHz-Sonographie die präoperative Lokalisation und Markierung von Mikroverkalkungsgruppen erleichtern?

PURPOSE: The value of 13 MHz ultrasound regarding the preoperative localisation in combination with mammography were investigated into. MATERIAL AND METHOD: Out of 112 mammaographically detected calcifications, 30 (30 patients) were clusters of microcalcifications. Out of these, 23 were classified as suspicious of malignancy and were preoperatively localised with a 7.5 and 13 MHz probe. Upon marking the skin, a fine needle was inserted, and after due correction blue dye or coal solution was instilled. RESULTS: Following mammographically shown position, 23 clusters of microcalcifications could be localised using the 13 MHz probe. A localisation with the 7.5 MHz probe was impossible in all cases. A single correction of the needle's site was necessary with 35% (8/23) of patients. The maximum distance of the needle's tip in case of misposition measured 11 mm. CONCLUSION: Giving a known mammographic position and a sonographic perceptibility of clusters of microcalcifications in a maximal depth of penetration of 2 cm, 13 MHz high resolution ultrasound examination in combination with mammography prove to be a valuable means in facilitating the preoperative localisation.

Resolution of several racemic 3-hydroxy-1,4-benzodiazepin-2-ones by high-performance liquid chromatography on a chiral silica-bonded stationary phase.

The resolution of four racemic 3-hydroxy-1,4-benzodiazepin-2-ones, widely used in therapeutics, by means of a chiral stationary phase is described. The chiral selector used is (S)-N-(3,5-dinitrobenzoyl)phenylalanine. This chiral stationary phase showed both good enantioselectivity and efficiency for the compounds. Elution times were in all cases shorter than those previously reported for such compounds on different stationary phases. Racemic oxazepam was used to evaluate the loading capacity of the chiral stationary phase.

[4 families with silent cholinesterase variant]. / Estudio de cuatro familias con variante colinesterásica silente.

We report 4 patients who had apnea of variable duration after succinylcholine administration to facilitate orotracheal intubation during anesthesia. After ruling out other causes of apnea unrelated to succinylcholine, we genotyped the cholinesterase variants of these patients and their relatives measuring total plasmatic cholinesterase activity and using the inhibitors dibucaine and fluoride. We found the silent gene (Es1) both in homozygosis (2 cases) and heterozygosis, with the atypical gene (Ea11) (2 cases). The relevance of preoperative screening to prevent anesthetic accidents is emphasized.

High resolution mass spectrometry in the identification of transformation products and metabolites from ß-lactam antibiotics in thermally treated milk.

Antibiotics such as ß-lactam derivatives (penicillins and cephalosporins) are frequently used in veterinary medicine. The presence of these antibiotics together with their metabolites and/or products produced in subsequent treatments at which milk is submitted (sterilization, pasteurization), may be responsible for bacterial resistance, allergy and/or toxicity on sensitive individuals. In this study, liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) is used to identify transformation products (TPs) from four ß-lactam antibiotics (amoxicillin (AMOX), cephapirin (PIR), ceftiofur (TIO) and penicillin G (PENG)) in thermally treated cow milk. In addition, milk from cows medicated with PENG has also been analogously treated and studied. The detected TPs come mainly from hydrolysis and decarboxylation reactions. Products more strongly degraded respect to parent compounds (of lower molecular weight) were obtained after treating milk at higher temperatures. Products identified in milk from cows medicated with PENG have been classified as TPs when coming from chemical/thermal degradation, and metabolites when resulting from the biological drug metabolism. While TPs are the result of hydrolysis and decarboxylation processes, as already indicated, an enzymatic conjugation with amino acids is suggested to be involved in the formation of metabolites.

[Clinical aspects and pathology of granulosa cell tumors. A single case report]. / Zur Klinik und Pathologie von Granulosazelltumoren. Eine Einzelkasuistik.

Case report on a granuloma cell tumour in a 82 year old patients. Because of estradiol production postmenopausal bleedings from a adenomatous-hyperplastic endometrium had been in the history. Hormonal values became normal following removal of the benign tumour in stage I. The most important pathologic, endocrinologic and therapeutical principles of the tumour have been described.