Pancreatic carcinoma, pancreatitis, and healthy controls: metabolite models in a three-class diagnostic dilemma

Metabolomics as one of the most rapidly growing technologies in the "-omics" field denotes the comprehensive analysis of low molecular-weight compounds and their pathways. Cancer-specific alterations of the metabolome can be detected by high-throughput mass-spectrometric metabolite profiling and serve as a considerable source of new markers for the early differentiation of malignant diseases as well as their distinction from benign states. However, a comprehensive framework for the statistical evaluation of marker panels in a multi-class setting has not yet been established. We collected serum samples of 40 pancreatic carcinoma patients, 40 controls, and 23 pancreatitis patients according to standard protocols and generated amino acid profiles by routine mass-spectrometry. In an intrinsic three-class bioinformatic approach we compared these profiles, evaluated their selectivity and computed multi-marker panels combined with the conventional tumor marker CA 19-9. Additionally, we tested for non-inferiority and superiority to determine the diagnostic surplus value of our multi-metabolite marker panels. Compared to CA 19-9 alone, the combined amino acid-based metabolite panel had a superior selectivity for the discrimination of healthy controls, pancreatitis, and pancreatic carcinoma patients [Formula: see text] We combined highly standardized samples, a three-class study design, a high-throughput mass-spectrometric technique, and a comprehensive bioinformatic framework to identify metabolite panels selective for all three groups in a single approach. Our results suggest that metabolomic profiling necessitates appropriate evaluation strategies and-despite all its current limitations-can deliver marker panels with high selectivity even in multi-class settings.

The Hungarian Economic Elite After the Political Transition

Erzsebet Szalai (Hungary). The Hungarian Economic Elite after the Political Transition. Ms. Szalai is a research fellow in the Institute of Political Sciences in Budapest and worked on this project from July 1996 to June 1998. In the period following the political changes of 1989, the leading forces of the economic elite have gained increasing superiority over the political and cultural elites, with the clear ambition of putting the latter to their service. The power relations within the economic elite were characterised by "a war of all against all". The desire to gain precedence over others became an openly declared value. The formation of estates and the intensification of competition became embodied in a multitude of lobbies which cropped up to assert short-term interests. After the state socialist period, possession of at least two of the social, economic and cultural forms of capital is necessary to join one of the three segments of the elite: political, cultural or economic. What defines the ability of the members of the three elite groups to assert their interests is their ability to convert any of the three types of capital into another. That is to say, the basis on which they can retain and extend their position is "symbolic capital" as interpreted by Bourdieu. The concept of symbolic capital is useful for describing the power relations following the collapse of state socialist systems and societies. In the state-socialist system, the political, economic and cultural spheres are tightly interwoven, and this interpenetration slackens only slowly after the system's disintegration. A close institutional relationship between the three spheres continues to make it easier for power actors to convert social, economic and cultural capital from one type to another. Symbolic capital, or the easy transfer between the three spheres, in turn reproduces the institutional relationship, or more precisely, complicates the separation of the three spheres after the fall of state socialism.

Dystonic movement disorders and spinal degenerative disease

The occurrence of degenerative spinal disease subsequent to dystonic movement disorders has been neglected and has received more attention only recently. Spinal surgery is challenging with regard to continuous mechanical stress when treatment of the underlying movement disorder is insufficient. To characterize better the particular features of degenerative spinal disease in patients with dystonia and to analyze operative strategies, we reviewed the available published data. Epidemiologic studies reveal that degenerative spinal disorders in patients with dystonia and choreoathetosis occur much earlier than in the physiological aging process. Dystonic movement disorders more often affect the spine at higher cervical levels (C(2-5)), in contrast to spinal degeneration with age which manifests more frequently at the middle and lower cervical spine (C(5-7)). Degenerative changes of the cervical spine are more likely to occur on the side where the chin is rotated or tilted to. Various operative approaches for treatment of spinal pathologies have been advocated in patients with dystonic movement disorders. The available data do not allow making firm statements regarding the superiority of one approach over the other. Posterior approaches were first used for decompression, but additional anterior fusion became necessary in many instances. Anterior approaches with or without instrumented fusion yielded more favorable results, but drawbacks are pseudarthrosis and adjacent-level disease. Parallel to the development of posterior fusion techniques, circumferential surgery was suggested to provide a maximum degree of cord decompression and a higher fusion rate. Perioperative local injections of botulinum toxin were used initially to enhance patient comfort with halo immobilization, but they are also applied in patients without external fixation nowadays. Treatment algorithms directed at the underlying movement disorder itself, taking advantage of new techniques of functional neurosurgery, combined with spinal surgery have recently been introduced and show promising results.

Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis

BACKGROUND AND PURPOSE: Basilar artery occlusion (BAO) is an infrequent form of acute stroke, which invariably leads to death or long-term disability if not recanalized. A traditional recanalization approach based on historical controls and pathophysiological consideration is local intra-arterial thrombolysis (IAT) in eligible patients. This necessitates diagnostic evaluation and treatment in stroke centers equipped with an interventional neuroradiological service on a 24-hour basis, but its superiority to the technically simple intravenous thrombolysis (IVT) remains unproven. METHODS: We analyzed systematically published case series of substantial size reporting the outcome of BAO after IAT or IVT. RESULTS: In 420 BAO patients treated with IVT (76) and IAT (344), death or dependency were equally common: 78% (59 of 76) and 76% (260 of 344), respectively (P=0.82). Recanalization was achieved more frequently with IAT (225 of 344; 65%) than with IVT (40 of 76; 53%; P=0.05), but survival rates after IVT (38 of 76; 50%) and IAT (154 of 344; 45%) were equal (P=0.48). A total of 24% of patients treated with IAT and 22% treated with IVT reached good outcomes (P=0.82). Without recanalization, the likelihood of good outcome was close to nil (2%). CONCLUSIONS: Recanalization occurs in more than half of BAO patients treated with IAT or IVT, and 45% to 55% of survivors regain functional independence. Although improved therapy forms for BAO are necessary, hospitals not equipped for IAT may set up IVT protocols. The effect of IVT is probably not much different from the effect of IAT. IVT represents probably the best treatment that can be offered to victims of acute BAO in such hospitals.

Integrated psychological therapy (IPT) for schizophrenia: is it effective?

Against the background of evidence-based treatments for schizophrenia, nowadays the implementation of specific cognitive and behavioral interventions becomes more important in the standard care of these patients. Over the past 25 years, research groups in 9 countries have carried out 30 independent evaluations of Integrated Psychological Therapy (IPT), a group program that combines neurocognitive and social cognitive interventions with social skills approaches for schizophrenic patients. The aim of the present study was to evaluate the effectiveness of IPT under varying treatment and research conditions in academic and nonacademic sites. In a first step, all 30 published IPT studies with the participation of 1393 schizophrenic patients were included in the meta-analysis. In a second step, only high-quality studies (HQS) (7 studies including 362 patients) were selected and analyzed to check whether they confirmed the results of the first step. Positive mean effect sizes favoring IPT over control groups (placebo-attention conditions, standard care) were found for all dependent variables, including symptoms, psychosocial functioning, and neurocognition. Moreover, the superiority of IPT continued to increase during an average follow-up period of 8.1 months. IPT obtained similarly favorable effects across the different outcome domains, assessment formats (expert ratings, self-reports, and psychological tests), settings (inpatient vs outpatient and academic vs nonacademic), and phases of treatment (acute vs chronic). The HQS confirmed the results of the complete sample. The analysis indicates that IPT is an effective rehabilitation approach for schizophrenia that is robust across a wide range of patients and treatment conditions.

Application and comparison of classification algorithms for recognition of Alzheimer's disease in electrical brain activity (EEG)

The early detection of subjects with probable Alzheimer's disease (AD) is crucial for effective appliance of treatment strategies. Here we explored the ability of a multitude of linear and non-linear classification algorithms to discriminate between the electroencephalograms (EEGs) of patients with varying degree of AD and their age-matched control subjects. Absolute and relative spectral power, distribution of spectral power, and measures of spatial synchronization were calculated from recordings of resting eyes-closed continuous EEGs of 45 healthy controls, 116 patients with mild AD and 81 patients with moderate AD, recruited in two different centers (Stockholm, New York). The applied classification algorithms were: principal component linear discriminant analysis (PC LDA), partial least squares LDA (PLS LDA), principal component logistic regression (PC LR), partial least squares logistic regression (PLS LR), bagging, random forest, support vector machines (SVM) and feed-forward neural network. Based on 10-fold cross-validation runs it could be demonstrated that even tough modern computer-intensive classification algorithms such as random forests, SVM and neural networks show a slight superiority, more classical classification algorithms performed nearly equally well. Using random forests classification a considerable sensitivity of up to 85% and a specificity of 78%, respectively for the test of even only mild AD patients has been reached, whereas for the comparison of moderate AD vs. controls, using SVM and neural networks, values of 89% and 88% for sensitivity and specificity were achieved. Such a remarkable performance proves the value of these classification algorithms for clinical diagnostics.

[Effectiveness of Integrated Psychological Therapy for schizophrenia patients : A meta-analysis including 28 independent studies.]

Over the past 24 years, research groups in eight different countries have conducted 28 independent evaluation studies on Integrated Psychological Therapy (IPT) including 1,329 schizophrenia patients. The present study examines the effectiveness of IPT under different treatment conditions by means of a meta-analytic review. The most salient results indicate favourable mean effect sizes for IPT in comparison to control groups (placebo-attention conditions, standard care). Moreover, the superiority of IPT continues to increase during an average catamnestic phase of 8.1 months. The method obtains similarly favourable effects in different functional areas (neurocognition, social behaviour, psychopathology) and different assessment formats (expert ratings, self-reports, psychological tests). The comparison of different settings of IPT and control groups shows the superiority of IPT in any given therapy or site condition. The analysis of subsamples of inpatients, outpatients, and patients in varying rehabilitation phases reveals similarly favourable effects. Comparing only high-quality studies yields comparable results. In summary, the present meta-analysis corroborates evidence that IPT is an 'empirically validated treatment' according to American Psychiatric Association guidelines.

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

PURPOSE: Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [68Ga-DOTA,Tyr3]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. METHODS: Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. RESULTS: All peptides showed high affinities on hsst2, with the highest affinity for the Ga(III)-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga(III) peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all 67Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the 111In-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [67Ga-DOTA,1-Nal3]octreotide in comparison to [111In-DOTA,1-Nal3]octreotide and [67Ga-DOTA,Tyr3]octreotide showed a significantly higher and receptor-mediated uptake of the two 67Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. CONCLUSION: This study demonstrates that 67/68Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the 111In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies.

Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia

Early allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as primary treatment modality for patients with chronic myeloid leukemia (CML). This concept has been challenged by transplantation mortality and improved drug therapy. In a randomized study, primary HSCT and best available drug treatment (IFN based) were compared in newly diagnosed chronic phase CML patients. Assignment to treatment strategy was by genetic randomization according to availability of a matched related donor. Evaluation followed the intention-to-treat principle. Six hundred and twenty one patients with chronic phase CML were stratified for eligibility for HSCT. Three hundred and fifty four patients (62% male; median age, 40 years; range, 11-59 years) were eligible and randomized. One hundred and thirty five patients (38%) had a matched related donor, of whom 123 (91%) received a transplant within a median of 10 months (range, 2-106 months) from diagnosis. Two hundred and nineteen patients (62%) had no related donor and received best available drug treatment. With an observation time up to 11.2 years (median, 8.9 years), survival was superior for patients with drug treatment (P = .049), superiority being most pronounced in low-risk patients (P = .032). The general recommendation of HSCT as first-line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first.

Within-subject comparison of two rigid bar designs connecting two interforaminal implants: patients' satisfaction and prosthetic results

BACKGROUND: There is evidence for the superiority of two-implant overdentures over complete dentures in the mandible. Various anchorage devices were used to provide stability to overdentures. The aim of the present study was to compare two designs of a rigid bar connecting two mandibular implants. MATERIALS AND METHODS: Completely edentulous patients received a new denture in the maxilla and an implant-supported overdenture in the mandible. They were randomly allocated to two groups (A or B) with regard to the bar design. A standard U-shaped bar (Dolder bar) was used connecting the two implants in a straight line. For comparison, precision attachments were soldered distal to the bar copings. Group A started the study with the standard bar (S-bar), while group B started with the attachment-bar (A-bar). After 3 months, they had to answer a questionnaire (visual analogue scale [VAS]); then the bar design was changed in both groups. After a period of another 3 months, the patients had to answer the same questions; then they had the choice to keep their preferred bar. Now the study period was extended to another year of observation, and the patients answered again the same questionnaire. In vivo force measurements were carried out with both bar types at the end of the test periods. The prosthetic maintenance service carried out during the 6-month period was recorded for both bar types in both groups. Statistical analysis as performed with the SPSS statistical package (SPSS Inc., Chicago, IL, USA). RESULTS: Satisfaction was high in both groups. Group B, who had entered the study with the attachment bar, gave slightly better ratings to this type for four items, while in group A, no differences were found. At the end of the 6-month comparison period, all but one patient wished to continue to wear the attachment bar. Prosthetic service was equal in groups A and B, but the total number of interventions is significantly higher in the attachment bar. Force patterns of maximum biting were similar in both bar designs, but exhibited significantly higher axial forces in the attachment bar. CONCLUSIONS: Both bar designs provide good retention and functional comfort. High stability appears to be an important factor for the patients' satisfaction and oral comfort. Rigid retention results in a higher force impact and appears to evoke the need for the retightening of occlusal screws, resulting in more maintenance service.

Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial

BACKGROUND: A novel stent platform eluting biolimus, a sirolimus analogue, from a biodegradable polymer showed promising results in preliminary studies. We compared the safety and efficacy of a biolimus-eluting stent (with biodegradable polymer) with a sirolimus-eluting stent (with durable polymer). METHODS: We undertook a multicentre, assessor-blind, non-inferiority study in ten European centres. 1707 patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes were centrally randomised by a computer-generated allocation sequence to treatment with either biolimus-eluting (n=857) or sirolimus-eluting (n=850) stents. The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation within 9 months. Analysis was by intention to treat. 427 patients were randomly allocated to angiographic follow-up, with in-stent percentage diameter stenosis as principal outcome measure at 9 months. The trial is registered with ClinicalTrials.gov, number NCT00389220. FINDINGS: We analysed all randomised patients. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents for the primary endpoint at 9 months (79 [9%] patients vs 89 [11%], rate ratio 0.88 [95% CI 0.64-1.19], p for non-inferiority=0.003, p for superiority=0.39). Frequency of cardiac death (14 [1.6%] vs 21 [2.5%], p for superiority=0.22), myocardial infarction (49 [5.7%] vs 39 [4.6%], p=0.30), and clinically-indicated target vessel revascularisation (38 [4.4%] vs 47 [5.5%], p=0.29) were similar for both stent types. 168 (79%) patients in the biolimus-eluting group and 167 (78%) in the sirolimus-eluting group had data for angiographic follow-up available. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents in in-stent percentage diameter stenosis (20.9%vs 23.3%, difference -2.2% [95% CI -6.0 to 1.6], p for non-inferiority=0.001, p for superiority=0.26). INTERPRETATION: Our results suggest that a stent eluting biolimus from a biodegradable polymer represents a safe and effective alternative to a stent eluting sirolimus from a durable polymer in patients with chronic stable coronary artery disease or acute coronary syndromes. FUNDING: Biosensors Europe SA, Switzerland.

Cognitive functioning, behavior, and quality of life after stroke in childhood

Rationale: To provide a better understanding of cognitive functioning, motor outcome, behavior and quality of life after childhood stroke and to study the relationship between variables expected to influence rehabilitation and outcome (age at stroke, time elapsed since stroke, lateralization, location and size of lesion). Methods: Children who suffered from stroke between birth and their eighteenth year of life underwent an assessment consisting of cognitive tests (WISC-III, WAIS-R, K-ABC, TAP, Rey-Figure, German Version of the CVLT) and questionnaires (Conner's Scales, KIDSCREEN). Results: Twenty-one patients after stroke in childhood (15 males, mean 11;11 years, SD 4;3, range 6;10-21;2) participated in the study. Mean Intelligence Quotients (IQ) were situated within the normal range (mean Full Scale IQ 96.5, range IQ 79-129). However, significantly more patients showed deficits in various cognitive domains than expected from a healthy population (Performance IQ p = .000; Digit Span p = .000, Arithmetic's p = .007, Divided Attention p = .028, Alertness p = .002). Verbal IQ was significantly better than Performance IQ in 13 of 17 patients, independent of the hemispheric side of lesion. Symptoms of ADHD occurred more often in the patients' sample than in a healthy population (learning difficulties/inattention p = .000; impulsivity/hyperactivity p = .006; psychosomatics p = .006). Certain aspects of quality of life were reduced (autonomy p = .003; parents' relation p = .003; social acceptance p = .037). Three patients had a right-sided hemiparesis, mean values of motor functions of the other patients were slightly impaired (sequential finger movements p = .000, hand alternation p = .001, foot tapping p = .043). In patients without hemiparesis, there was no relation between the lateralization of lesion and motor outcome. Lesion that occurred in the midst of childhood (5-10 years) led to better cognitive outcome than lesion in the very early (0-5 years) or late childhood (10-18 years). Other variables such as presence of seizure, elapsed time since stroke and size of lesion had a small to no impact on prognosis. Conclusion: Moderate cognitive and motor deficits, behavioral problems, and impairment in some aspects of quality of life frequently remain after stroke in childhood. Visuospatial functions are more often reduced than verbal functions, independent of the hemispheric side of lesion. This indicates a functional superiority of verbal skills compared to visuospatial skills in the process of recovery after brain injury. Compared to the cognitive outcome following stroke in adults, cognitive sequelae after childhood stroke do indicate neither the lateralization nor the location of the lesion focus. Age at stroke seems to be the only determining factor influencing cognitive outcome.

Parotid tumors: fine-needle aspiration and/or frozen section

OBJECTIVE: The purpose of this study was to analyze and compare the value of fine-needle aspiration cytology (FNAC) and frozen section (FS) analysis in the assessment of parotid gland tumors. STUDY DESIGN: Chart review and cross-sectional analysis. SUBJECTS AND METHODS: FNAC and FS analysis of 110 parotid tumors, 68 malignancies and 42 benign tumors, were analyzed and compared with the final histopathologic diagnosis. RESULTS: The accuracy, sensitivity, and specificity of FNAC in detecting malignant tumors were 79 percent, 74 percent, and 88 percent, respectively. On FS analysis, the accuracy, sensitivity, and specificity in detecting malignant tumors were 94 percent, 93 percent, and 95 percent, respectively. The histologic tumor type was correctly diagnosed by FNAC and FS in 27 of 42 (64%) and 39 of 42 (93%) benign tumors, respectively, and in 24 of 68 (35%) and 49 of 68 (72%) malignant neoplasms, respectively. CONCLUSION: The current analysis showed a superiority of FS compared with FNAC regarding the diagnosis of malignancy and tumor typing. FNAC alone is not prone to determine the surgical management of parotid malignancies.

Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides

PURPOSE: G protein-coupled receptor agonists are being used as radiolabeled vectors for in vivo localization and therapy of tumors. Recently, somatostatin-based antagonists were shown to be superior to agonists. Here, we compare the new [111In/68Ga]-labeled bombesin-based antagonist RM1 with the agonist [111In]-AMBA for targeting the gastrin-releasing peptide receptor (GRPR). EXPERIMENTAL DESIGN: IC50, Kd values, and antagonist potency were determined using PC-3 and HEK-GRPR cells. Biodistribution and imaging studies were done in nude mice transplanted with the PC-3 tumor. The antagonist potency was assessed by evaluating the effects on calcium release and on receptor internalization monitored by immunofluorescence microscopy. RESULTS: The IC50 value of [(nat)In]-RM1 was 14 +/- 3.4 nmol/L. [(nat/111)In]-RM1 was found to bind to the GRPR with a Kd of 8.5 +/- 2.7 nmol/L compared with a Kd of 0.6 +/- 0.3 nmol/L of [111In]-AMBA. A higher maximum number of binding site value was observed for [111In]-RM1 (2.4 +/- 0.2 nmol/L) compared with [111In]-AMBA (0.7 +/- 0.1 nmol/L). [(nat)Lu]-AMBA is a potent agonist in the immunofluorescence-based internalization assay, whereas [(nat)In]-RM1 is inactive alone but efficiently antagonizes the bombesin effect. These data are confirmed by the calcium release assay. The pharmacokinetics showed a superiority of the radioantagonist with regard to the high tumor uptake (13.4 +/- 0.8% IA/g versus 3.69 +/- 0.75% IA/g at 4 hours after injection. as well as to all tumor-to-normal tissue ratios. CONCLUSION: Despite their relatively low GRPR affinity, the antagonists [111In/68Ga]-RM1 showed superior targeting properties compared with [111In]-AMBA. As found for somatostatin receptor-targeting radiopeptides, GRP-based radioantagonists seem to be superior to radioagonists for in vivo imaging and potentially also for targeted radiotherapy of GRPR-positive tumors.

Ridge preservation techniques for implant therapy

PURPOSE: The aim of this review was to evaluate the techniques and outcomes of postextraction ridge preservation and the efficacy of these procedures in relation to subsequent implant placement. MATERIALS AND METHODS: A MEDLINE/PubMed search was conducted and the bibliographies of reviews from 1999 to March 2008 were assessed for appropriate studies. Randomized clinical trials, controlled clinical trials, and prospective/retrospective studies with a minimum of five patients were included. RESULTS: A total of 135 abstracts were identified, from which 53 full-text articles were further examined, leading to 37 human studies that fulfilled the search criteria. Many different techniques, methodologies, durations, and materials were presented in the publications reviewed, making direct comparison difficult. CONCLUSIONS: Despite the heterogeneity of the studies, it was concluded that ridge preservation procedures are effective in limiting horizontal and vertical ridge alterations in postextraction sites. There is no evidence to support the superiority of one technique over another. There is also no conclusive evidence that ridge preservation procedures improve the ability to place implants.