Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology.

Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.

Acromelic frontonasal dysostosis and ZSWIM6 mutation: phenotypic spectrum and mosaicism.

Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling.

Chitin-calcium alginate composite fibers for wound care dressings spun from ionic liquid solution.

Chitin-calcium alginate composite fibers were prepared from a solution of high molecular weight chitin extracted from shrimp shells and alginic acid in the ionic liquid 1-ethyl-3-methylimidazolium acetate by dry-jet wet spinning into an aqueous bath saturated with CaCO3. The fibers exhibited a significant proportion of the individual properties of both calcium alginate and chitin. Ultimate stress values were close to values obtained for calcium alginate fibers, and the absorption capacities measured were consistent with those reported for current wound care dressings. Wound healing studies (rat model, histological evaluation) indicated that chitin-calcium alginate covered wound sites underwent normal wound healing with re-epithelialization and that coverage of the dermal fibrosis with hyperplastic epidermis was consistently complete after only 7 days of treatment. Using a single patch per wound per animal during the entire study, all rat wounds achieved 95-99% closure by day 10 with complete wound closure by day 14.

Rhizobium radiobacter as an opportunistic pathogen in central venous catheter-associated bloodstream infection: case report and review.

Rhizobium radiobacter is an uncommon opportunistic pathogen present in soil. It has been particularly associated with indwelling intravascular devices in immunocompromised patients. In this report, we summarise the case of a patient with multiple myeloma who developed R. radiobacter bacteraemia during autologous stem cell leucopheresis. Retrospective investigation revealed exposure to soil after central venous catheter placement for chemotherapy and leucopheresis access. This is the first reported case of R. radiobacter bacteraemia following probable colonisation of the catheter from soil exposure. We further review the existing literature to delineate prevention and treatment recommendations for line-associated R. radiobacter infections.

Akathisia--seen from the patients' perspective.

Akathisia is a side-effect that continues to affect a large percentage of psychiatric patients though the focus over recent years has moved away from extrapyramidal side-effects to metabolic problems. As cognitive behavioural therapy has become an integrated part of the management plan for psychotic patients an increased understanding of patients' interpretation of their symptoms and side-effects are encouraged. This case series illustrates different views that patients take on medication induced side-effects.

Does a positive end-expiratory pressure-induced reduction in stroke volume indicate preload responsiveness? An experimental study.

BACKGROUND: Increases in positive end-expiratory pressure (PEEP) are often associated with cardiovascular depression, responding to fluid loading. Therefore, we hypothesized that if stroke volume (SV) is reduced by an increase in PEEP this reduction is an indicator of hypovolemia or preload responsiveness, i.e. that SV would increase by fluid administration at zero end-expiratory pressure (ZEEP). The relationship between the cardiovascular response to different PEEP levels and fluid load as well as the relation between change in SV as a result of change in preload (Frank-Starling relationship) were evaluated in a porcine model. In addition, other measures of fluid status were assessed. METHODS: Eight, 20-22 kg, anesthetized, mechanically ventilated pigs were subjected to 0, 10, and 20 cm H(2)O PEEP at 10% (of estimated blood volume) hypovolemia, normo- and 10% hypervolemia, and to ZEEP at 20% hypervolemia. SV, cardiac output, intrathoracic blood volume and airway, esophageal, vascular pressures, stroke volume variations, left ventricular end-diastolic and end-systolic areas and respiratory variations in the diameter of the inferior vena cava were obtained. RESULTS: At hypovolemia and normovolemia, 10 cm H(2)O PEEP induced a significant decrease in SV, while no change occurred at 10% hypervolemia. SV measured at ZEEP increased from hypovolemia to normovolemia and 10% hypervolemia, while no change was found between 10% and 20% hypervolemia. The sensitivity and specificity decrease in SV by PEEP indicating an increase in SV by fluids was 60-88% and 67%, respectively, depending on the volemic (preload) levels. CONCLUSION: Although the overall results suggest that a change in SV by PEEP might predict preload responsiveness, the individual response of SV by 10 cm H(2)O PEEP and of the successive fluid administration seemed to be dependent on where on the Frank-Starling curve the heart function was located.

The misdiagnosis of epilepsy in children admitted to a tertiary epilepsy centre with paroxysmal events.

AIMS: To determine the proportion of children admitted with difficult to treat paroxysmal events to a tertiary epilepsy centre who did not have epilepsy. METHODS: In an observational retrospective study, all case notes of 223 children admitted in 1997 were examined. The referral was made from the local paediatric department in 51% of cases, other departments in 27%, and from general or specialist practitioners in 22%. Doubt regarding the diagnosis of epilepsy was expressed in the referral note in 17%. On admission, 86% were on antiepileptic drug treatment. During admission all children were subjected to a comprehensive intensive observation and 62% had EEG monitoring. RESULTS: In total, 39% (87/223) were found not to have epilepsy. In 30% of children (55/184) referred without any doubts about the epilepsy diagnosis, the diagnosis was disproved. Of the 159 children admitted for the first time, 75 (47%) were discharged with a diagnosis of non-epileptic seizures. Of 125 children admitted for the first time with no doubts about the diagnosis of epilepsy, 44 (35%) did not have epilepsy. Staring episodes were the most frequently encountered non-epileptic paroxysmal event. Psychogenic non-epileptic seizures were found in 12 children. A total of 34 (15%) had their medication tapered off; a further 22 (10%) had tapered off medication before admission. CONCLUSION: The present study supports the view that misdiagnosis of epilepsy is common. The treating physician should be cautious in diagnosis, especially of staring episodes. A diagnostic re-evaluation should be undertaken in difficult cases with continuing paroxysmal events in order to avoid unnecessary drug treatment and restrictions on the child's lifestyle.

Pigmentary mosaicism with mosaic chromosome 5p tetrasomy.

Pigmentary mosaicism with mosaic chromosome 5p tetrasomy is described. A 5-year-old girl had phylloid hyperpigmentation segregated in the midline, and neurological deficits. Chromosome analysis performed on blood lymphocytes was normal, whereas skin fibroblasts from affected skin areas revealed chromosomal mosaicism.

Perfusion quantification using Gaussian process deconvolution.

The quantification of perfusion using dynamic susceptibility contrast MRI (DSC-MRI) requires deconvolution to obtain the residual impulse response function (IRF). In this work, a method using the Gaussian process for deconvolution (GPD) is proposed. The fact that the IRF is smooth is incorporated as a constraint in the method. The GPD method, which automatically estimates the noise level in each voxel, has the advantage that model parameters are optimized automatically. The GPD is compared to singular value decomposition (SVD) using a common threshold for the singular values, and to SVD using a threshold optimized according to the noise level in each voxel. The comparison is carried out using artificial data as well as data from healthy volunteers. It is shown that GPD is comparable to SVD with a variable optimized threshold when determining the maximum of the IRF, which is directly related to the perfusion. GPD provides a better estimate of the entire IRF. As the signal-to-noise ratio (SNR) increases or the time resolution of the measurements increases, GPD is shown to be superior to SVD. This is also found for large distribution volumes.

Long-term enhancement of cytochrome P450 2B1/2 expression in rat hepatocyte spheroids through adenovirus-mediated gene transfer.

Tissue-like structures of cells organized in vitro have a great potential for a number of clinical and biomedical applications. Cell functions may be modulated with gene delivery, improving the characteristics of these structures. Hepatocytes that self-assemble into spheroids can be transduced through adenovirus-mediated gene transfer. An adenoviral vector (AdGFP) was employed to deliver a gene encoding for green fluorescent protein (GFP) in rat hepatocyte spheroids. GFP fluorescence was detected for at least one month. Furthermore, the rat cytochrome P450 2B1 gene (CYP2B1) was transferred through infection with a recombinant adenovirus (AdCYP2B1) in hepatocyte spheroids cultured in suspension. The CYP2B1/2 mRNA and apoprotein levels were continuously higher for over 23 days compared to phenobarbital-induced and control cultures. P450-catalyzed pentoxyresorufin-O-dealkylation activity was also high in the AdCYP2B1-infected spheroids. In these spheroid cultures, albumin and urea levels were similar to those in uninfected spheroid cultures, indicating that expression of the CYP2B1 transgene did not impair these liver-specific functions. Hepatocyte spheroids transduced by recombinant adenoviral vectors can be efficiently used for drug metabolism studies, in implantation, and in bioartificial liver devices.

The quantitative evaluation of functional neuroimaging experiments: mutual information learning curves.

Learning curves are presented as an unbiased means for evaluating the performance of models for neuroimaging data analysis. The learning curve measures the predictive performance in terms of the generalization or prediction error as a function of the number of independent examples (e.g., subjects) used to determine the parameters in the model. Cross-validation resampling is used to obtain unbiased estimates of a generic multivariate Gaussian classifier, for training set sizes from 2 to 16 subjects. We apply the framework to four different activation experiments, in this case [(15)O]water data sets, although the framework is equally valid for multisubject fMRI studies. We demonstrate how the prediction error can be expressed as the mutual information between the scan and the scan label, measured in units of bits. The mutual information learning curve can be used to evaluate the impact of different methodological choices, e.g., classification label schemes, preprocessing choices. Another application for the learning curve is to examine the model performance using bias/variance considerations enabling the researcher to determine if the model performance is limited by statistical bias or variance. We furthermore present the sensitivity map as a general method for extracting activation maps from statistical models within the probabilistic framework and illustrate relationships between mutual information and pattern reproducibility as derived in the NPAIRS framework described in a companion paper.

The methanol hemisolvate of amiloride hydrochloride.

In the asymmetric unit of N-(3,5-diamino-6-chloropyrazin-2-ylcarbonyl)-N-(diaminomethylene)ammonium chloride methanol hemisolvate, C(6)H(9)ClN(7)O(+).Cl(-).0.5CH(4)O, there are two crystallographically different amiloride molecules. Crystallographically identical amiloride molecules are stacked one above the other, alternately rotated by 180 degrees. These stacks are arranged parallel to each other, forming layer A. The least-squares plane of the non-H atoms of the other molecules lying in layer B is tilted against the corresponding plane of the molecules in layer A by an angle of 79.89 (3) degrees. The methanol molecules and Cl(-) anions are located between these layers, although the methanol molecules are closer to layer A.

Consensus inference in neuroimaging.

We introduce model averaging in neuroimaging. We show that model summary images can be directly compared and averaged after histogram equalization. We demonstrate that averaging enhances the ROC curve in a simulation study. The averaging procedure is applied to a fMRI study of motor cortex.

Feature-space clustering for fMRI meta-analysis.

Clustering functional magnetic resonance imaging (fMRI) time series has emerged in recent years as a possible alternative to parametric modeling approaches. Most of the work so far has been concerned with clustering raw time series. In this contribution we investigate the applicability of a clustering method applied to features extracted from the data. This approach is extremely versatile and encompasses previously published results [Goutte et al., 1999] as special cases. A typical application is in data reduction: as the increase in temporal resolution of fMRI experiments routinely yields fMRI sequences containing several hundreds of images, it is sometimes necessary to invoke feature extraction to reduce the dimensionality of the data space. A second interesting application is in the meta-analysis of fMRI experiment, where features are obtained from a possibly large number of single-voxel analyses. In particular this allows the checking of the differences and agreements between different methods of analysis. Both approaches are illustrated on a fMRI data set involving visual stimulation, and we show that the feature space clustering approach yields nontrivial results and, in particular, shows interesting differences between individual voxel analysis performed with traditional methods.

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2.

Cells in culture become competent to replicate in the absence of growth factor after progressing beyond the late G1 restriction point, suggesting that a set of genes expressed during G1 phase is sufficient to trigger completion of the cell cycle. However, this has not been demonstrated in an in vivo system. In this study, we examined whether transfection of genes associated with the G1/S transition could trigger hepatocyte replication. Co-transfection of cyclin E and skp2 synergistically promoted cell cycle progression in cultured primary hepatocytes in the absence of mitogen or in the presence of growth inhibitors. Furthermore, transfection of hepatocytes in vivo with cyclin E and skp2 promoted abundant hepatocyte replication and hyperplasia of the liver. These studies confirm that transfection with a small number of genes can trigger proliferation of quiescent hepatocytes in vivo, and suggest that therapies to enhance liver regeneration by targeting cell cycle control genes may be feasible.

A temperature-sensitive disorder in basal transcription and DNA repair in humans.

The xeroderma pigmentosum group D (XPD) helicase subunit of TFIIH functions in DNA repair and transcription initiation. Different mutations in XPD give rise to three ultraviolet-sensitive syndromes: the skin cancer-prone disorder xeroderma pigmentosum (XP), in which repair of ultraviolet damage is affected; and the severe neurodevelopmental conditions Cockayne syndrome (CS) and trichothiodystrophy (TTD). In the latter two, the basal transcription function of TFIIH is also presumed to be affected. Here we report four unusual TTD patients with fever-dependent reversible deterioration of TTD features such as brittle hair. Cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermo-instability of TFIIH. Our findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes in humans, which previously were only known in lower organisms.

The role of actin filaments and microtubules in hepatocyte spheroid self-assembly.

Cultured rat hepatocytes self-assemble into three-dimensional structures or spheroids that exhibit ultrastructural characteristics of native hepatic tissue and enhanced liver-specific functions. The spheroid formation process involves cell translocation and changes in cell shape, indicative of the reorganization of the cytoskeletal elements. To elucidate the function of the cytoskeleton, hepatocytes undergoing spheroid formation were treated with drugs that disrupt the different cytoskeletal components. Cytochalasin D, which targets the actin filaments, caused inhibition of spheroid formation. The role of microtubules in this process was assessed by incubating the cells with taxol or nocodazole. Perturbation of microtubules had minimal effects on spheroid assembly. Scanning electron micrographs showed no morphological differences between spheroids formed in control cultures and those formed in the presence of taxol or nocodazole. In addition, the effects of those agents on hepatocyte functions were investigated. Albumin secretion and cytochrome P450 2B1/2 activities of hepatocytes were comparable in spheroids formed in the presence of taxol or nocodazole to those formed in control cultures. The levels of these liver-specific activities were lower in cytochalasin D--treated cultures where only dispersed cells or cell clumps were found but spheroids had not found. Thus, hepatocytes require an intact actin network to self-assemble efficiently into functional tissue-like structures. Perturbation of the microtubule lattice does not impair the formation process. Events that transpire during hepatocyte spheroid self-assembly exhibit striking similarities to processes commonly observed in tissue morphogenesis. The results provide insight into the mechanisms that cells employ to organize into tissues and can contribute to our understanding of how to control the cellular assembly in tissue engineering and clinical applications.

High prevalence of coeliac disease in Danish children with type I diabetes mellitus.

UNLABELLED: The purpose of this population-based study was to determine the prevalence of coeliac disease (CD) in 106 Danish children (age 2-18 y) with type I diabetes mellitus compared with 106 age- and sex-matched healthy controls. Serum samples were analysed for immunoglobulin A (IgA) and IgG gliadin antibodies by enzyme-linked immunosorbent assay (ELISA), for IgA endomysium antibodies (EMA) by immunofluorescence and for IgA tissue transglutaminase antibodies (tTGA) by ELISA. None of the controls had EMA or tTGA. Two diabetics previously diagnosed with CD were antibody negative on a gluten-free diet. Ten diabetics had both EMA and tTGA. Intestinal biopsy was performed in nine of them. All biopsies showed a histological picture of partial or total villous atrophy confirming the diagnosis of CD. Diabetics with CD were significantly younger (p = 0.026). had an earlier onset of diabetes (p = 0.005), had a lower height standard deviation score (p = 0.019) and more often had thyroid antibodies (p = 0.040) compared with diabetics without CD. CONCLUSION: A high prevalence of CD of 10.4% (95% confidence interval 4.6-16.2%) was found in young Danish diabetics. Early onset of diabetes may predispose to CD. Routine serological screening for CD may be valuable in patients with type I diabetes mellitus.

[Zellweger syndrome--a peroxisomal disease]. / Zellwegers syndrom--en peroxisomal sygdom.

Zellweger syndrome is a fatal recessively inherited disease with disturbed function of many organs. The disease is caused by a defect of peroxisomes, subcellular organelles, which are absent in these patients. Several genes are necessary for the formation and function of the peroxisomes. The clinical picture of Zellweger syndrome can be caused by defects in a number of genes. On the other hand, clinically different diseases such as neonatal adrenoleucodystrophy and infantile Refsum disease have been shown to be allelic to Zellweger syndrome. We describe a typical Zellweger patient belonging to complementation group 1, which is by far the largest group containing more than half of the Zellweger patients.

Evaluation of the effect of culture matrices on induction of CYP3A isoforms in cultured porcine hepatocytes.

Several bioartificial liver devices have been developed as temporary therapy for patients suffering from fulminant hepatic failure. Some of these devices contain porcine hepatocytes entrapped in collagen matrices. In order to improve the function of these BAL devices, there exists a need to optimize metabolic function of cultured hepatocytes. The goal of these investigations was to evaluate the effect of altering culture conditions on rifampin-mediated induction of CYP3A isoforms in cultured porcine hepatocytes. Midazolam metabolism was compared in porcine hepatocytes cultured in a monolayer configuration on collagen gels, in a sandwich configuration between collagen gels and a Matrigel overlay, and in spheroidal cultures. The effect of culture conditions was evaluated, by measuring CYP3A-mediated metabolism of midazolam and by immunoblotting to detect CYP3A proteins, in control cultures and in rifampin-treated cultures. Results obtained by normalizing the metabolism rate data to cell numbers (based on DNA content) present at the end of the culture experiment, showed that there was no difference between the different culture conditions tested. Our results suggest that culturing porcine hepatocytes as spheroids or in a sandwich configuration between collagen and Matrigel, offers no advantage in terms of CYP3A-mediated metabolic function on a per cell basis compared to culturing on collagen gels.