Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

BACKGROUND AND AIMS: Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. METHODS: To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. RESULTS: The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. CONCLUSION: The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered by drugs or disease. The model can be extended to describe completely the metabolism and enterohepatic circulation of any bile acids in man in health and digestive disease. The model should also be broadly applicable to the description of the pharmacokinetics of all other drugs whose metabolism is similar to that of bile acids, i.e., drugs for which there are tissue and bacterial biotransformations, enterohepatic cycling, and appreciable first-pass clearance.

Effects of nifedipine on functional liver plasma flow in normal subjects and in patients with cirrhosis.

The short-term effects of nifedipine (10 mg administered sublingually) on functional liver plasma flow, measured by calculating the extrarenal clearance of sorbitol, were investigated in 12 normal volunteers and 40 patients with cirrhosis scored according to Child-Pugh classification. Nifedipine significantly increased functional liver plasma flow in healthy subjects (23%, p < 0.0001) and in patients with cirrhosis in the Child-Pugh class A group (19%, p < 0.001); in patients in the Child-Pugh class B group functional liver plasma flow was not modified, whereas in the patients in the Child-Pugh class C group it was significantly reduced (-7%, p < 0.02). The mean arterial pressure showed a significant reduction in all groups studied. According to the pathophysiologic meaning of functional liver plasma flow, it is suggested that nifedipine meets criteria for an ideal test substance to evaluate the functional reserve of the liver. Furthermore, when used with the Child-Pugh classification, its effect on functional liver plasma flow may be useful to improve the efficiency of the Child-Pugh classification, in establishing the prognosis of patients with cirrhosis.

Assessment of functional liver mass and plasma flow in acromegaly before and after long-term treatment with octreotide.

Functional liver mass and functional liver plasma flow (FLPF) were assessed in 11 patients with clinical features of acromegaly by determining galactose elimination capacity (GEC) and extrarenal clearance of sorbitol, before and 5 to 7 months after treatment with the long-acting somatostatin analog, octreotide (150 to 600 micrograms/d in three subcutaneous injections). Growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, as well as liver size by ultrasound, were also recorded. Baseline GEC was increased in every patient but one, for a mean of 0.78 +/- 0.10 g/min (normal, 0.53 +/- 0.07; P < .01). At reevaluation after 5 to 7 months of octreotide treatment, a significant reduction of GEC was observed (0.62 +/- 0.08 g/min, P < .001). Changes of GEC paralleled those of GH (38.6 +/- 34.4 v 11.7 +/- 15.2 micrograms/L, P < .01) and IGF-I (5.0 +/- 1.7 v 2.7 +/- 2.2 U/ml, P < .001). Significant correlations were found between GEC and GH (r = .50, P < .05) and between GEC and IGF-I (r = .55, P < .01). FLPF, assessed by extrarenal clearance of sorbitol, was within the normal limit in all cases (0.98 +/- 0.19 v 0.97 +/- 0.12 L/min, NS) and remained normal after 5 to 7 months of octreotide treatment (0.99 +/- 0.11 L/min). Hepatic structure determined with ultrasonic scanning and conventional liver-function tests were basally normal in all patients, with a slight increase of liver volume in three cases. No change of biochemical and/or morphological features occurred during follow-up evaluation. The results support the hypothesis that GH and especially IGF-I enhance liver metabolic capacity; conversely, functional liver perfusion is largely independent of their actions. Our data also suggest that octreotide is unable to produce well-structured changes of liver circulation when administered long-term.

Hepatic arterial infusion chemotherapy for unresectable confined liver metastases: prediction of systemic toxicity with the application of a scintigraphic and pharmacokinetic approach.

PURPOSE: The incorrect positioning of the arterial Port-a-Cath or the presence of anatomic or functional hepatic arteriovenous shunting may explain the occurrence of systemic toxicity of hepatic arterial infusion of floxuridine in patients with liver metastases. The aim of our study was to predict the occurrence of systemic toxic effects from this treatment using a scintigraphic and pharmacokinetic approach. METHODS: A group of 26 patients were studied. Before treatment, Tc-99m-labelled macroaggregated albumin arterial perfusion scintigraphy was performed to verify the correct positioning of the catheter, to evaluate the percentage of pulmonary uptake of the tracer, reflecting intrahepatic arteriovenous anatomic shunting, and to qualitatively assess the perfusion pattern of the metastases with respect to the normal liver parenchyma (SPECT images). Hepatic arteriovenous functional shunting was assessed through the bioavailability of intraarterially administered D-sorbitol. Treatment was then started and systemic toxic effects were evaluated according to WHO recommendations. RESULTS: No correlation was found between anatomic shunting (

Emerging risk factors and assessment of organ damage in postmenopausal hypertensive women.

The numerous risk factors for acute cerebrocardiovascular events present in postmenopausal women have attracted a multidisciplinary approach. In hypertensive patients and postmenopausal intensive alike, the need for stratification of risk based on blood pressure, association of other risk factors and organ damage is becoming more and more evident. This study investigated some emerging factors, such as endothelial dysfunction, adhesion molecules and elevated homocysteine levels that may be markers of organ damage. It also examined the current importance of carotid US intima-media thickness assessment, cardiac US imaging and 24 hour ambulatory blood pressure monitoring (ABPM) in detecting organ damage. The study results indicated that the conventional stratification of cerebrocardiovascular risk in these patients is changing. The new approach in postmenopausal hypertensives tends to assess the presence of other emerging factors. Furthermore, assessment of organ damage is crucial for determining disease development and outcome that may be positively influenced by suitable pharmacological treatment.

Evaluation of the diagnostic value of serum bile acid in the detection and functional assessment of liver diseases.

The diagnostic usefulness of fasting total serum bile acids (SBA/F) in the detection of liver diseases and assessment of different aspects of hepatic function alteration was evaluated in 61 healthy subjects and 186 patients with liver disease. The value of SBA/F was compared with other routine tests. In 49 healthy subjects and 92 patients, serum bile acids were also measured after the im administration of Ceruletide as a cholecystokinetic agent (SBA/C). The diagnostic efficacy for the detection of disease states was better with aspartate-aminotransferase (EC 2.6.1.1) and alanine-aminotransferase (EC 2.6.1.2) than with SBA/F. When SBA/C was also determined the diagnostic efficacy was not substantially better than the SBA/F test. In the assessment of hepatocellular necrosis SBA/F showed a higher rate of misclassification errors compared to alanine-aminotransferase (mean error 45% vs 17%), whereas SBA/F gave similar results with direct bilirubin and pseudocholinesterase (EC 3.1.1.8) in the evaluation of cholestasis (mean error 40% vs 41%) and impaired biosynthesis (mean error 39% vs 40%), respectively. Serum bile acid determination did not show any significant diagnostic advantage with respect to the other routine liver tests.

A modular approach for representing and executing clinical guidelines.

In this paper, we propose an approach for managing clinical guidelines. We outline a modular architecture, allowing us to separate two conceptually distinct aspects: the representation (and acquisition) of clinical guidelines and their execution. We propose an expressive formalism, which allows one to deal with the context-dependent character of clinical guidelines and also takes into account different temporal aspects. We also describe our tool for acquiring clinical guidelines, which provides a user-friendly interface to physicians, and automatically detects many forms of syntactic and semantic inconsistencies in the guidelines being acquired. In the second part of the paper, we describe a flexible engine for executing clinical guidelines (e.g. for clinical decision support applications, for medical education, or for integrating guidelines into the clinical practice), focusing our attention on temporal issues.

Hyperhomocysteinemia in preeclampsia is associated to higher risk pressure profiles.

Homocysteine levels have been determined with Chromatography on HPLC column, between the 20th and the 24th week of pregnancy, in women with analogous characteristics (a) normotensive, (b) with pregnancy-induced hypertension (PIH), low (LR), medium (MR), high risk (HR). The group they belonged to was confirmed after natural or caesarean delivery. All the patients were submitted to 24 hour blood pressure monitoring for the evaluation of further pressure risk parameters: mean arterial pressure (MAP), non dippers, percentages of pressure peaks. Homocysteine levels in normotensive pregnant women (5.8 +/- 1.7 microM) were low. Significant high levels of homocysteine were present proportionally to the risk degree of PIH. Higher levels of homocysteine statistically significant were present in non dippers of all groups (MR p < 0.05; HR p < 0.01). A direct correlation between plasmatic homocisteine levels and pressure profiles was found out in non dippers (r = 0.56, r = 0.55, r = 0.50 respectively) and in dippers (r = 0.7, r = 0.75, r = 0.60 respectively), and also between levels of homocysteine, MAP value, and pathological percentages of systolic and diastolic nocturnal peaks. In pregnant women presenting preeclampsia afterwards, high levels of homocysteine were not different from mean values present in high risk PIH pregnant women (13.3 +/- 1.9 vs. 16.4 +/- 1.7 microM). High levels of homocysteine early determined in the second trimester of PIH pregnancies seem to be associated to a pregnancy higher risk, coexisting with dangerous pressure profiles. High levels confirm a pregnant woman to belong to a higher or lower risk degree of vascular damage, but in the same group context high levels of homocisteine do not allow to identify those pregnant women who will develop eclampsia.

Hyperhomocysteinemia in menopausal hypertension: an added risk factor and a dangerous association for organ damage.

Hyperhomocysteinemia is widely recognised as an emerging risk factor of endothelial dysfunction and vascular damage. In this study we wanted to verify if it, when associated to arterial hypertension--traditional risk factor--represents a higher added risk of organ damage during menopause, which is a condition connected to a higher incidence of cerebrovascular diseases. A survey of 30 postmenopausal women with similar characteristics (BMI, age, absence of relevant pathologies such as diabetes, metabolic disorders and absence of smoking) was selected (menopause had occurred from 12 to 16 months at the moment of observation). At the moment of the observation they had not gone through any continuous pharmacological therapy. They were subdivided into 3 groups: normotensive; hypertensive (with 2nd degree hypertension: mild to moderate) without organ damage; hypertensive with organ damage (TIA, ischaemic heart disease, etc.). The carotid IMT, measured with ultrasound method, was considered as an organ damage parameter. 43% of the patients had high levels of homocysteine (> 15 micromol/l), which are levels considered at risk in other surveys. The highest levels of homocysteine were recorded in hypertensive women with episodes of acute cerebrovascular damage (micromol/l = 24.3 +/- 8.9). In this group, a positive correlation (r = 0.7) was obtained between homocysteine levels and carotid IMT. The possible coexistence of hyperhomocysteinemia and arterial hypertension, even though without particularly high values for both of them, in menopause may represent a dangerous association responsible for a significant organ damage and, therefore, for acute cerebrovascular events.

LIED--liver: information, education and diagnosis.

In this paper we describe LIED (Liver: Information, Education and Diagnosis), a diagnostic expert system devoted to medical education in the field of hepatology. LIED combines the facilities of a traditional expert system for clinical diagnosis with several modules designed for educational purposes. The goal of such modules is to train physicians, in particular as regards the improvement of their problem solving ability (at the end of their curricula students in medicine usually lack experience in organizing an efficient and accurate diagnostic process). Training on real and simulated cases has been widely recognized as a proper approach to clinical experience. The architecture of the diagnostic system is introduced, which forms the core of LIED, and which has been derived from our previous experience, and the various educational functions are discussed that were developed on top of the basic architecture.

Computer-aided diagnosis in jaundice: comparison of knowledge-based and probabilistic approaches.

The study reported in this paper is aimed at evaluating the effectiveness of a knowledge-based expert system (ICTERUS) in diagnosing jaundiced patients, compared with a statistical system based on probabilistic concepts (TRIAL). The performances of both systems have been evaluated using the same set of data in the same number of patients. Both systems are spin-off products of the European project Euricterus, an EC-COMAC-BME Project designed to document the occurrence and diagnostic value of clinical findings in the clinical presentation of jaundice in Europe, and have been developed as decision-making tools for the identification of the cause of jaundice based only on clinical information and routine investigations. Two groups of jaundiced patients were studied, including 500 (retrospective sample) and 100 (prospective sample) subjects, respectively. All patients were independently submitted to both decision-support tools. The input of both systems was the data set agreed within the Euricterus Project. The performances of both systems were evaluated with respect to the reference diagnoses provided by experts on the basis of the full clinical documentation. Results indicate that both systems are clinically reliable, although the diagnostic prediction provided by the knowledge-based approach is slightly better.

Validation of ICTERUS, a knowledge-based expert system for Jaundice diagnosis.

The study aimed to describe an example of the assessment and validation of knowledge-based clinical expert systems. The paper focuses on ICTERUS, an expert system for jaundice diagnosis. It describes system design, the methodology applied for upgrading and validating the program, and the most important outcomes of the validation procedure. The clinical validation of the system on a very large European database (Euricterus Project) shows that diagnostic conclusions are reliable in about 70% of eligible cases. This figure appears acceptable for a system which provides decision support only on the basis of clinical data, assuming that the final decision is achieved under user responsibility. Expected biases, limitations and inconsistencies in the practical application of the system are discussed.

Clinical database. Structure, development strategies and expected clinical applications.

The paper provides the description of a data-base developed to include in a quite structured format most clinical data used for patient management in a hospital setting. The system was aimed at achieving a reasonable compromise between the significant but complex solutions the research offers and the real needs of medical practice. First of all, the paper defines the requirements for designing a computerized clinical database according to a patient-centered clinical approach. Then, it describes the structure of a prototype aimed at classifying clinical data as a hierachy and describing them according to a structural approach. Next, problems related to the management and upgrading of the system are identified and possible solutions described, with a particular emphasis or knowledge acquisition, refinement and specialization, and on problems related to the functional aspects required for clinical applications. Finally, some meaningful clinical applications are outlined, which use the computerized clinical database as the standard for knowledge organization and data sharing.

An electronic medical diary for computer assisted patient management.

The Electronic Medical Diary (EMD) is a tool for supporting the daily registration and storage of clinical events related to a specific patient. The collection of all patient-specific clinical data forms the patient database (PDB) which can be defined as a computer-based record able to replace the traditional paper record. The PDB is organized according to the clinical database (CDB), which is a structured terminology of most important clinical data, and may be connected with the many online tools (OLT) which can improve the flow of information within the hospital information system (HIS). In this paper we present the preliminary results of a project aimed at creating an EMD designed in accordance with the methodological model based on the problem-oriented approach. This EMD is patient-centered and each action it enables is related to at least one of the identified problems and one of the current diagnostic hypotheses. The permanent link of the EMD with the CDB is one of the most important features of the prototype here described. It allows the standardization of patients' data, their sharing among all operators involved, and a better organization of the patient management process.

[Pathophysiological and therapeutic implications of nitric oxide in hepatology]. / Implicazioni fisiopatologiche e terapeutiche del monossido di azoto in epatologia.

The L-arginine/nitric oxide (NO) pathway has been recognized as a main regulator of several cell functions. Accordingly, there is an increasing number of pathophysiological conditions in which a precise knowledge of NO status could prove helpful in understanding the mechanisms involved in disease development, prevention and treatment. These include several hepatic disorders, such as liver cirrhosis and associated hyperdynamic circulation with portal hypertension, ischaemia-reperfusion injury occurring during liver transplantation, and chronic cholestatic conditions. Overall, NO seems to exert a dual role in the pathobiology of liver diseases: one mostly beneficial, due to its vasoactive effects; and one mostly negative, due to its local toxic effects. Protective actions are primarily mediated via vasodilation, antithrombosis, inhibition of neutrophil adhesion and inhibition of apoptosis. Deleterious effects are dependent upon the formation of highly reactive substances during oxidative stress. In this review aspects related to NO implications in the homeostasis of liver functions as well as in the pathogenesis of some relevant hepatic clinical syndromes will be discussed in view of possible therapeutic options.

PEPTY: a knowledge-based program for assisting medical reasoning in peptic diseases.

PEPTY is a program developed with the aim of providing a diagnostic and therapeutic assistance in managing peptic diseases. Its theoretical basis is an accurate analysis of current concepts in peptic disease diagnosis and treatment. This was done by reviewing recent literature and consulting skilled gastroenterologists. The decision tree includes three sections dealing with diagnostic, therapeutic and monitoring problems. The diagnostic section starts by evaluating clinical data from patient history and physical examination; the diagnostic hypotheses given at this level are refined and eventually confirmed by further information in the following section. Here the decision tree becomes modular in that a proper therapeutic and monitoring pathway is defined for four disease classes: gastroduodenal peptic ulcer and duodenitis, gastro-oesophageal reflux, erosive gastritis, and chronic antral gastritis. In the therapeutic section a cost-benefit analysis of possible therapeutic choices is always performed, but the final decision is made by the user. Complications, side effects and treatment efficacy are also considered and the program finally suggests the appropriate maintenance treatment. Patient data display, storage and retrieval, and explanation facilities are supplied. The system can provide a 'second opinion' in the medical practice and may be a useful learning tool for medical students.

Prediction by mathematical simulation of different pathophysiological effects on D-sorbitol bioavailability.

In this study a mathematical model was applied to predict how changes in hepatic extraction ratio (E), fractional portal inflow (P) and renal elimination ratio (R) may affect fractional D-sorbitol bioavailability in cirrhotic patients. D-sorbitol bioavailability was computed as the ratio between cumulative urinary outputs measured after infusion into the superior mesenteric (Uma) or the hepatic artery (Uha) and a systemic vein (Usv). The present work was aimed at explaining by mathematical simulation the very large difference observed in the regression lines when plotting Uma or Uha against Usv values. The study was performed by considering a pathophysiological model of the hepatic circulation and simulating independent variations of the above considered parameters or assuming particular pathophysiological conditions like hepatic arterialization and hepatofugal flow. Computational results account for the wide dispersion of experimental data obtained in previous studies and provide reasonable explanations of unexpected findings.

Pirenzepine does not impair liver blood flow in the rat.

The present study was performed with the aim of establishing whether the muscarinic-receptor antagonist pirenzepine impairs liver blood flow, as previously observed for H2-blockers. For this purpose, two different doses of pirenzepine (0.3 and 0.6 mg/100 g b.w. respectively) were administered to two groups of rats. Liver plasma flow was measured 30 min after treatment by the new sorbitol clearance test which is simple and does not require hepatic vein catheterization. The results were compared with those obtained in a control group and in a group treated with cimetidine. It was shown that, compared to the control group in which the observed functional liver plasma flow was 5.0 +/- 1.3 ml/min/100 g b.w. (MV +/- SD), rats treated with either dose of pirenzepine showed no significant impairment of liver perfusion. On the other hand, cimetidine treatment produced a significant reduction (p less than 0.001) of functional liver plasma flow. Our results show that pirenzepine treatment does not significantly impair liver functional activity through reduced liver perfusion. They also suggest that muscarinic receptors are probably not involved in the control of splanchnic blood flow.

[HEPASCORE: a decision-support system for the identification, clinical staging and functional assessment of hepatopathies]. / HEPASCORE: un sistema di supporto alla decisione per l'identificazione, la stadiazione clinica e la valutazione funzionale delle epatopatie.

A decision support system (HEPASCORE) has been developed to optimize the application of objective criteria for qualitative and quantitative assessment of liver function; clinical and laboratory data are automatically processed, and conclusions are explained. Early recognition of abnormal liver states is performed according to a sequential approach, based at first on clinical rules utilizing data from history and physical examination, then confirming or denying the hypothesis by means of selected laboratory tests. Once an abnormal condition is defined, clinical severity can be evaluated by use of suitable scores, either prognostic or focused on major clinical complications. In addition, selected sets of biochemical tests can be used to score one or more functional aspects. Lastly, whenever quantitative estimates of residual liver function are requested, dynamic tests can be applied to measure meaningful parameters such as functioning liver mass and functional hepatic plasma flow. HEPASCORE has been successfully applied to exclude liver abnormalities in subjects at risk, to follow up liver patients, to predict the natural outcomes of severe liver diseases, to foresee the adverse effects of drugs undergoing first-pass liver extraction and the side effects of invasive procedures. While the proposals contained in the system could be further modified for specific needs, they reflect a satisfactory methodological approach, and the program serves as a useful support to decisions regarding the identification and functional evaluation of hepatopathies. The system was developed with Microsoft Access 7.0 and runs on a personal computer under Windows 95.