Development of a clinical hepatic encephalopathy staging scale.

AIM: To develop a scale to assess the severity of hepatic encephalopathy using simple dichotomic items. METHODS: A list of 48 items was created by selecting items that are simple to recognize and categorize; it was applied to thirty-six cirrhotic in-patients with episodic encephalopathy, in addition to the adapted-West-Haven Criteria and the Glasgow Coma Score. The list underwent an item reduction process and principal component analysis; the metric characteristics were evaluated. RESULTS: Multiple neurological abnormalities were observed and a Clinical Hepatic Encephalopathy Staging Scale of nine items was constructed. The principal component analysis of the Clinical Hepatic Encephalopathy Staging Scale obtained two factors that explained 77% of the variance. The Clinical Hepatic Encephalopathy Staging Scale exhibited adequate internal consistency and reproducibility. The scores of the Clinical Hepatic Encephalopathy Staging Scale correlated to those of adapted-West-Haven Criteria and the Glasgow Coma Score. CONCLUSIONS: This study confirms that the evaluation of multiple neurological manifestations is not necessary to classify hepatic encephalopathy adequately, which can be simply undertaken by an assessment of the patient's orientation, alertness, ability to respond to commands and to talk. A list of nine items is proposed as a linear scale from normality (Clinical Hepatic Encephalopathy Staging Scale = 0) to deep coma (Clinical Hepatic Encephalopathy Staging Scale = 9).

Correlation between morphological MRI findings and specific diagnostic categories in fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) include physical and neurodevelopmental abnormalities related to prenatal alcohol exposure. Some neuroimaging findings have been clearly related to FASD, including corpus callosum and cerebellar anomalies. However, detailed studies correlating with specific FASD categories, that is, the fetal alcohol syndrome (FAS), partial FAS (pFAS) and alcohol related neurodevelopmental disorders (ARND), are lacking. We prospectively performed clinical assessment and brain MR imaging to 72 patients with suspected FASD, and diagnosis was confirmed in 62. The most frequent findings were hypoplasia of the corpus callosum and/or of the cerebellar vermis. Additional findings were vascular anomalies, gliosis, prominent perivascular spaces, occipito-cervical junction and cervical vertebral anomalies, pituitary hypoplasia, arachnoid cysts, and cavum septum pellucidum.

Conformation-dependent QSAR approach for the prediction of inhibitory activity of bromodomain modulators.

Epigenetic drug discovery is a promising research field with growing interest in the scientific community, as evidenced by the number of publications and the large amount of structure-epigenetic activity information currently available in the public domain. Computational methods are valuable tools to analyse and understand the activity of large compound collections from their structural information. In this manuscript, QSAR models to predict the inhibitory activity of a diverse and heterogeneous set of 88 organic molecules against the bromodomains BRD2, BRD3 and BRD4 are presented. A conformation-dependent representation of the chemical structures was established using the RDKit software and a training and test set division was performed. Several two-linear and three-linear QuBiLS-MIDAS molecular descriptors ( www.tomocomd.com ) were computed to extract the geometric structural features of the compounds studied. QuBiLS-MIDAS-based features sets, to be used in the modelling, were selected using dimensionality reduction strategies. The multiple linear regression procedure coupled with a genetic algorithm were employed to build the predictive models. Regression models containing between 6 to 9 variables were developed and assessed according to several internal and external validation methods. Analyses of outlier compounds and the applicability domain for each model were performed. As a result, the models against BRD2 and BRD3 with 8 variables and the model with 9 variables against BRD4 were those with the best overall performance according to the criteria accounted for. The results obtained suggest that the models proposed will be a good tool for studying the inhibitory activities of drug candidates against the bromodomains considered during epigenetic drug discovery.

Tensor algebra-based geometric methodology to codify central chirality on organic molecules.

A novel mathematical procedure to codify chiral features of organic molecules in the QuBiLS-MIDAS framework is introduced. This procedure constitutes a generalization to that commonly used to date, where the values 1 and -1 (correction factor) are employed to weight the molecular vectors when each atom is labelled as R (rectus) or S (sinister) according to the Cahn-Ingold-Prelog rules. Therefore, values in the range [Formula: see text] with steps equal to 0.25 may be accounted for. The atoms labelled R or S can have negative and positive values assigned (e.g. -3 for an R atom and 1 for an S atom, or vice versa), opposed values (e.g. -3 for an R atom and 3 for an S atom, or vice versa), positive values (e.g. 3 for an R atom and 1 for an S atom) or negative values (e.g. -3 for an R atom and -1 for an S atom). These proposed Chiral QuBiLS-MIDAS 3D-MDs are real numbers, non-symmetric and reduced to 'classical' (non-chiral) QuBiLS-MIDAS 3D-MDs when symmetry is not codified (correction factor equal to zero). In this report, only the factors with opposed values were considered with the purpose of demonstrating the feasibility of this proposal. From QSAR modelling carried out on four chemical datasets (Cramer's steroids, fenoterol stereoisomer derivatives, N-alkylated 3-(3-hydroxyphenyl)-piperidines, and perindoprilat stereoisomers), it was demonstrated that the use of several correction factors contributes to the building of models with greater robustness and predictive ability than those reported in the literature, as well as with respect to the models exclusively developed with QuBiLS-MIDAS 3D-MDs based on the factor 1 | -1. In conclusion, it can be stated that this novel strategy constitutes a suitable alternative to computed chirality-based descriptors, contributing to the development of good models to predict properties depending on symmetry.

N-tuple topological/geometric cutoffs for 3D N-linear algebraic molecular codifications: variability, linear independence and QSAR analysis.

Novel N-tuple topological/geometric cutoffs to consider specific inter-atomic relations in the QuBiLS-MIDAS framework are introduced in this manuscript. These molecular cutoffs permit the taking into account of relations between more than two atoms by using (dis-)similarity multi-metrics and the concepts related with topological and Euclidean-geometric distances. To this end, the kth two-, three- and four-tuple topological and geometric neighbourhood quotient (NQ) total (or local-fragment) spatial-(dis)similarity matrices are defined, to represent 3D information corresponding to the relations between two, three and four atoms of the molecular structures that satisfy certain cutoff criteria. First, an analysis of a diverse chemical space for the most common values of topological/Euclidean-geometric distances, bond/dihedral angles, triangle/quadrilateral perimeters, triangle area and volume was performed in order to determine the intervals to take into account in the cutoff procedures. A variability analysis based on Shannon's entropy reveals that better distribution patterns are attained with the descriptors based on the cutoffs proposed (QuBiLS-MIDAS NQ-MDs) with regard to the results obtained when all inter-atomic relations are considered (QuBiLS-MIDAS KA-MDs - 'Keep All'). A principal component analysis shows that the novel molecular cutoffs codify chemical information captured by the respective QuBiLS-MIDAS KA-MDs, as well as information not captured by the latter. Lastly, a QSAR study to obtain deeper knowledge of the contribution of the proposed methods was carried out, using four molecular datasets (steroids (STER), angiotensin converting enzyme (ACE), thermolysin inhibitors (THER) and thrombin inhibitors (THR)) widely used as benchmarks in the evaluation of several methodologies. One to four variable QSAR models based on multiple linear regression were developed for each compound dataset following the original division into training and test sets. The results obtained reveal that the novel cutoff procedures yield superior performances relative to those of the QuBiLS-MIDAS KA-MDs in the prediction of the biological activities considered. From the results achieved, it can be suggested that the proposed N-tuple topological/geometric cutoffs constitute a relevant criteria for generating MDs codifying particular atomic relations, ultimately useful in enhancing the modelling capacity of the QuBiLS-MIDAS 3D-MDs.

Technetium-99m-HMPAO brain SPECT in Behçet's disease.

UNLABELLED: Behçet's disease (BD) is an idiopathic multisystem disorder. Involvement of the central nervous system (CNS) occurs in 4%-48% of cases. The aim of this study was to evaluate 99mTc-hexamethyl propyleneamine oxime (HMPAO) SPECT findings in BD patients and eventually to detect CNS involvement by depicting cerebral blood flow disturbances. METHODS: Technetium-99m-HMPAO brain SPECT was performed on 33 consecutive BD patients. Qualitative and quantitative evaluation of the cortical uptake was done using an automatic program that generated 32 regions of interest (ROIs). An uptake index for each ROI was obtained. Reference values were obtained from a healthy control group (n = 20). Twenty-five patients also had an MRI study. RESULTS: Twelve of 32 patients (36%) presented with a clinical neurological disorder. SPECT and visual evaluation revealed that 17 patients (51.5%) had abnormalities; 9 of 25 MRI studies (36%) were abnormal. Using the quantitative approach for SPECT, 23 patients (69.7%) had abnormally low values. Six of 12 patients with neurological symptoms had a visually abnormal SPECT scan, whereas quantitative analysis showed abnormalities in 11 patients. Of the 21 patients with no neurological findings, 9 had abnormal SPECT results, and 12 had low uptake indexes. CONCLUSION: HMPAO brain SPECT shows high rates of cerebral blood flow abnormalities in BD patients presenting with neuropsychiatric symptoms, and it also is frequently abnormal in asymptomatic BD patients who have no abnormalities on MR scans. Compared with visual analysis, quantitative analysis detects an even higher rate of SPECT changes in BD patients.

[Comparative effectiveness of alpha-2 adrenergic agonists (clonidine-guanfacine) in the hospital detoxification of opiate addicts]. / Eficacia comparada de agonistas alpha 2-adrenérgicos (clonidina-guanfacina) en la desintoxicación hospitalaria de adictos a opiáceos.

The usefulness of two alpha-2 adrenergic agonists (clonidine and guanfacine) and their comparative effectiveness were evaluated regarding the control of the opiates abstinence syndrome and the secondary effects, including development of cardiovascular abnormalities, in 88 parenteral heroin abusers admitted to two hospital units for the treatment of addiction. The patients were treated in a random, double blind fashion, with clonidine or guanfacine. In the study dosages, both drugs proved to be useful to control the abstinence syndrome. Nearly 70% of those treated with any of the two agonists were able to complete the treatment. When both drugs were compared, a higher degree of restlessness (p less than 0.01) was found among those treated with clonidine, although there were no differences in any other evaluated parameters to compare the degree of abstinence in each drug. The most commonly found side effects were orthostatism, lassitude, mental torpor and oral xerosis. These were independent of the drug used. There were no differences between both drugs regarding heart rate or blood pressure, although both parameters were significantly modified with the doses used in the study.

[Immunoglobulin A and human immunodeficiency virus type 1 infection in parenteral drug abuse addicts]. / Inmunoglobulina A e infección por el virus de la inmunodeficiencia humana tipo 1 en adictos a drogas por vía parenteral.

BACKGROUND: To evaluate the usefulness of serum immunoglobulin A (IgA) as a prognostic marker of human immunodeficiency virus type 1 (HIV-1) in parenteral drug abusers (PDA). METHODS: The serum IgA levels and HIV-1 antibodies were assessed in 374 PDAs admitted for infective diseases or for treatment of addiction. RESULTS: The prevalence of HIV infection was 70%; the frequency of serum IgA above the upper normal limit (440 mg/dl) was 8% in seronegative and 4% in seropositive subjects (NS). The IgA levels in the 274 seropositive subjects, classified for infective stages, were significantly higher in those fulfilling the criteria for acquired immunodeficiency syndrome (AIDS) or AIDS related complex (group IV) than in asymptomatic subjects (group II) or in those with generalized lymphadenopathy (group III) (p less than 0.01). CONCLUSIONS: Serum IgA levels in PDAs with HIV infection may be a useful marker of progression to AIDS.

Biexponential analysis of diffusion-tensor imaging of the brain in patients with cirrhosis before and after liver transplantation.

BACKGROUND AND PURPOSE: DTI has shown increased MD of water molecules in the brain of patients with cirrhosis, consistent with low-grade edema. This study further characterizes this edema by using biexponential analysis of DTI data, a technique that may differentiate cytotoxic and vasogenic edema. MATERIALS AND METHODS: A total of 41 patients with cirrhosis awaiting liver transplantation and 16 healthy controls were studied by DTI by using a single-shot echo-planar technique with 11 b-values (range, 0-7500 s/mm(2)) and 6 noncollinear directions. Measurements were fitted to biexponential function to determine MD and FA for the fast and slow diffusion components. Regions of interest were selected in the parietal white matter and corticospinal tract. The assessment was repeated 1 year after liver transplantation in 24 of these patients. RESULTS: In parietal white matter, patients with cirrhosis showed an increase in fast MD and a decrease in fast FA that normalized after liver transplantation. In the corticospinal tract, there was an increase in fast and slow MD that normalized after transplantation, and a decrease in FA that persisted posttransplantation. There was no association of DTI parameters with minimal HE (n =12). CONCLUSIONS: Biexponential analysis of DTI supports the presence of edema in the brain of patients with cirrhosis that reverts after transplantation. In parietal white matter, the increase in brain water was mainly located in the interstitial compartment, while the corticospinal tract showed a mixed pattern (intra- and extracellular). In addition, the findings on posttransplantation were consistent with microstructural damage along the corticospinal tract.

Sjögren's syndrome: histologic and immunohistochemical study.

Labial salivary gland tissues from 20 patients with primary Sjögren's syndrome (group 1), 26 with the secondary type of the disease (group 2), 16 patients with the incomplete form of the disease and 10 normal controls were examined for the presence of lymphocyte infiltrates, epithelial damages and plasma cell aggregates. Activated T lymphocytes of the helper phenotype predominated in groups 1 and 2. Aberrant epithelial expression of HLA class II molecules was found in the same group of patients, while IgG- and IgM- containing plasma cells were detected.

Natural history of parenteral drug addicts treated in a general hospital.

The progress of 298 heroin addicts treated for different reasons in a general hospital from 1984 to 1987 is followed, in order to know the remission degree of parenteral drug use and mortality rates in heroin abusers, after being treated for organic diseases or undergoing quick detoxification treatment. After an average of 25 months since their first visit or admission, information was obtained in 90% of the cases, and of these, it was confirmed that 4% (11/266) had died and that 6% (15/255) were in prison. Of the remainder, reliable information was obtained from 66% (158/240), of whom 40% were no longer endovenous drug users, while 54% were still addicted to parenteral drugs. The results showed a higher percentage of remission in patients that had been admitted for organic diseases (39/65; 60%) than in those that had been treated for detoxification (30/93; 35%) (p less than 0.05).

The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation.

BACKGROUND/AIMS: Liver failure may cause brain edema through an increase in brain glutamine. However, usually standard neuroimaging techniques do not detect brain edema in cirrhosis. We assessed magnetization transfer ratio and (1)H-magnetic resonance (MR) spectroscopy before and after liver transplantation to investigate changes in brain water content in cirrhosis. METHODS: Non-alcoholic cirrhotics without overt hepatic encephalopathy (n=24) underwent (1)H-MR of the brain and neuropsychological tests. (1)H-MR results were compared with those of healthy controls (n=10). In a subgroup of patients (n=11), the study was repeated after liver transplantation. RESULTS: Cirrhotic patients showed a decrease in magnetization transfer ratio (31.5+/-3.1 vs. 37.1+/-1.1, P<0.01) and an increase in glutamine/glutamate signal (2.22+/-0.47 vs. 1.46+/-0.26, P<0.01). The increase in glutamine/glutamate signal was correlated to the decrease in magnetization transfer ratio and to neuropsychological function. Following liver transplantation, there was a progressive normalization of magnetization transfer ratio, glutamine/glutamate signal and neuropsychological function. Accordingly, correlations between these variables were lost after liver transplantation. CONCLUSIONS: Cirrhotic patients show reversible changes in magnetization transfer ratio that are compatible with the development of low-grade cerebral edema. Minimal hepatic encephalopathy and low-grade cerebral edema appear to be the consequences of the metabolism of ammonia in the brain.