Multimodal data fusion of cortical-subcortical morphology and functional network connectivity in psychotic spectrum disorder.

Multiple authors have noted overlapping symptoms and alterations across clinical, anatomical, and functional brain features in schizophrenia (SZ), schizoaffective disorder (SZA), and bipolar disorder (BPI). However, regarding brain features, few studies have approached this line of inquiry using analytical techniques optimally designed to extract the shared features across anatomical and functional information in a simultaneous manner. Univariate studies of anatomical or functional alterations across these disorders can be limited and run the risk of omitting small but potentially crucial overlapping or joint neuroanatomical (e.g., structural images) and functional features (e.g., fMRI-based features) which may serve as informative clinical indicators of across multiple diagnostic categories. To address this limitation, we paired an unsupervised multimodal canonical correlation analysis (mCCA) together with joint independent component analysis (jICA) to identify linked spatial gray matter (GM), resting-state functional network connectivity (FNC), and white matter fractional anisotropy (FA) features across these diagnostic categories. We then calculated associations between the identified linked features and trans-diagnostic behavioral measures (MATRICs Consensus Cognitive Battery, MCCB). Component number 4 of the 13 identified displayed a statistically significant relationship with overall MCCB scores across GM, resting-state FNC, and FA. These linked modalities of component 4 consisted primarily of positive correlations within subcortical structures including the caudate and putamen in the GM maps with overall MCCB, sparse negative correlations within subcortical and cortical connection tracts (e.g., corticospinal tract, superior longitudinal fasciculus) in the FA maps with overall MCCB, and negative relationships with MCCB values and loading parameters with FNC matrices displaying increased FNC in subcortical-cortical regions with auditory, somatomotor, and visual regions.

Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.

OBJECTIVE/BACKGROUND: The aim of the Carotid Alarm Study was to compare the procedural risk of carotid endarterectomy (CEA) performed within 48 hours with that after 48 hours to 14 days following an ipsilateral cerebrovascular ischaemic event. METHODS: Consecutive patients with symptomatic carotid stenosis undergoing CEA were prospectively recruited. Time to surgery was calculated as time from the most recent ischaemic event preceding surgery. A neurologist examined patients before and, after CEA. The primary endpoint was the composite endpoint of death and/or any stroke within 30 days of the surgical procedure. The study was designed to include 600 patients, with 150 operated on within 48 hours. RESULTS: From October 2010 to December 2015, 418 patients were included, of whom 75 were operated within 48 hours of an ischaemic event. The study was prematurely terminated owing to the slow recruitment rate in the group operated on within 48 hours. Patients undergoing CEA within 48 hours had a higher risk of reaching the primary endpoint than those operated on later (8.0% vs. 2.9%). Multivariate logistic regression analyses showed that CEA performed within 48 h (odds ratio [OR] 3.07; 95% confidence interval [CI] 1.04-9.09), CEA performed out of office hours (OR 3.65; 95% CI 1.14-11.67), and use of shunt (OR 4.02; 95% CI 1.36-11.93) were all independently associated with an increased risk of reaching the primary endpoint. CONCLUSION: CEA performed within 48 hours was associated with a higher risk of complications compared with surgery performed 48 hours-14 days after the most recent ischaemic event.

Risk of Recurrent Stroke in Patients with Symptomatic Mild (20-49% NASCET) Carotid Artery Stenosis.

OBJECTIVE: The objective of this study was to evaluate the risk of recurrent ischaemic stroke in patients with ultrasound assessed symptomatic mild carotid artery stenosis (20-49% NASCET) treated solely with modern medical treatment. METHOD: This was a retrospective, observational register cohort study. Three groups of patients were recruited from a database of all carotid Doppler ultrasound examinations performed in the Gothenburg region between 2004 and 2009. Patients with symptomatic mild carotid artery stenosis (n = 162) were compared with patients with asymptomatic carotid artery stenosis (n = 301) of equal degree and a group of patients with surgically (CEA) treated symptomatic moderate or severe carotid artery stenosis (n = 220). Kaplan-Meier estimates and Cox proportional hazard models were used to compare the primary outcome (ipsilateral ischaemic stroke) between groups. RESULTS: After a 3 year follow up, the cumulative incidence of recurrent ipsilateral stroke in patients with symptomatic mild carotid artery stenosis was 7.4%. Patients with symptomatic mild carotid artery stenosis had a substantially increased risk of recurrent ipsilateral stroke compared with asymptomatic patients with equal degree of stenosis (HR 5.5. 95% CI 1.8-17.1; p = .003) as also compared with patients with CEA treated symptomatic moderate or severe stenosis (HR 7.8. 95% CI 1.62-37.8; p = .011). CONCLUSIONS: The present study on patients with symptomatic mild carotid artery stenosis, as determined by Doppler ultrasound, shows that there is still a substantial risk of recurrent stroke in this group.

The relationship between mother to child calories served and maternal perception of hunger.

BACKGROUND: Research has examined self-serving portions in adults and children and has shown that larger portion size is related to more calories consumed. The present study examines factors that may influence the portion sizes a mother serves her child at a mealtime. METHODS: The present observational study included a community-based sample of 29 mother-child dyads. Dyads attended a 1-h session in which they shared a meal together. A buffet of food was provided and the mother was asked to serve her child and herself. The amount of food served and consumed by the child was recorded. Main independent variables of interest included maternal body mass index (BMI), child BMI Z-score, and maternal perception of personal and child hunger. The primary dependent variable was the total calories the mother served her child. Regression models and a moderated mediation were used to examine the relation between variables. RESULTS: Calories served to the child was positively associated with calories consumed by the child. Maternal perception of her own hunger was related to her perception of her child's hunger. Furthermore, maternal perception of child hunger explained the relationship between maternal perception of personal hunger and total calories served to the child, although only for obese mothers. CONCLUSIONS: Mothers may be serving their children larger portion sizes based on their personal weight and their perception of their child's hunger. To help children obtain or maintain a healthy weight, obesity prevention and intervention programmes should help mothers serve more appropriate serving sizes to their children.

Risk of early recurrent stroke in symptomatic carotid stenosis.

OBJECTIVES: The risk of recurrent stroke in patients with symptomatic carotid artery stenosis is highest in the first weeks after a transient ischemic attack (TIA) or minor stroke and can be reduced with carotid endarterectomy (CEA). The optimal timing of CEA remains a controversial issue since very urgent CEA is associated with an increased procedural risk. The aim of this study was to determine the risk of very early recurrent stroke in a population with symptomatic high grade carotid stenosis. METHODS: Data were analyzed on all patients with ocular TIA, TIA, or minor stroke with >70% carotid stenosis as assessed by carotid ultrasound at Sahlgrenska University Hospital during the periods 2004-2006 and 2010-2012. The two time periods were chosen to minimize selection bias and to analyze changes over time. The risk of recurrent stroke within 30 days of the referring event was assessed. RESULTS: 397 patients with symptomatic carotid stenosis were identified. The risk of recurrent stroke in the total cohort was 2.0% (CI 95% 0.6-3.4) by day 2, 4.0% (CI 95% 2.0-5.9) by day 7, and 7.5% (CI 95% 4.4-10.6) by day 30. There was no significant difference between the two time periods. Patients with minor stroke had a significantly higher risk of recurrent stroke than patients with TIA or ocular TIA as the referring event. CONCLUSIONS: The data suggest that the early risk of recurrent stroke in symptomatic significant carotid stenosis is not as high as some earlier studies have shown. The risk is similar to several studies in which a modern medical treatment regime could be assumed.

Computer simulation of control strategies for optimal anaerobic digestion.

Three previously published control strategies for anaerobic digestion were implemented in Simulink/Matlab using Anaerobic Digestion Model No. 1 (ADM1) to model the biological process. The controllers' performance were then simulated and evaluated based on their responses from five different types of process scenarios i.e. start-up and steady state performance as well as disturbances from concentration, pH and ammonia in the inflow. Of the three evaluated control strategies, the extremum-seeking variable gain controller gave the best overall performance. However, a proportional feedback controller based on the pH-level, used as a reference case in the evaluation, proved to give as good results as the extremum-seeking variable gain controller but with a lower wear on the pump. It was therefore concluded that a fast proportional control of the reactor pH is a key element for optimally controlling a low-buffering anaerobic digestion process.

Expression profiling of microdissected cell populations selected from basal cells in normal epidermis and basal cell carcinoma.

BACKGROUND: Basal cell carcinomas (BCCs) are prevalent tumours with uniform histology that develop without any known precursor lesion. Alterations in the sonic hedgehog-patched1 signalling pathway are accepted as necessary events for tumorigenesis, and mutations in the patched1 gene are frequently present in tumours. OBJECTIVES: To analyse transcript profiles in BCC. METHODS: We used laser-assisted microdissection to isolate and collect cell populations defined under the microscope. Peripheral cells from nests of BCC were selected to represent tumour cells, and normal keratinocytes from epidermis basal layer were used as control. Extracted RNA was amplified and hybridized on to a cDNA microarray. Results Our results show that BCC cells express a transcript signature that is significantly different from that of normal keratinocytes, and over 350 genes with various functions were identified as differentially expressed. The compiled data suggest an upregulation of the Wnt signalling pathway as a major event in BCC cells. Furthermore, tumour cells appear to have an increased sensitivity to oxygen radicals and dysregulated genes involved in antigen presentation. RESULTS: were validated at both the transcriptional level using real-time polymerase chain reaction and at the protein level using immunohistochemistry. CONCLUSIONS: We show that microdissection in combination with robust strategies for RNA extraction, amplification and cDNA microarray analysis allow for reliable transcript profiling and that antibody-based proteomics provides an advantageous strategy for the analysis of corresponding differentially expressed proteins. We found that expression patterns were significantly altered in BCC cells compared with basal keratinocytes and that the Wnt signalling pathway was upregulated in tumour cells.

Transcriptional enhancers of immunoglobulin light chain genes in Atlantic cod (Gadus morhua).

The organization of immunoglobulin heavy (H) chain genes in teleosts resembles that of mammals and amphibians, whereas light (L) chain genes are arranged in multiple clusters of variable (VL), joining (JL), and constant (CL) region segments. Sequence analysis of two Atlantic cod genomic clones (14,966 and 13,116 bp in length) revealed a very compact IgL chain locus with the VL genes in opposite transcriptional orientation to the JL and the CL genes. This suggests the possibility of rearrangements between clusters by inversion. Each cluster spans approximately 2.1 kb and distances between clusters vary between 2.1 and 4.8 kb. To gain insight into the transcriptional regulation of this complex, multiclustered locus, chloramphenicol acetyl transferase reporter constructs containing 14 different DNA segments from the two genomic clones were transfected into channel catfish B and non-B-cell lines, as well as into mouse B-cell lines. These studies showed strong enhancer activity downstream of the CL region in three out of six L chain gene clusters when assayed in fish, but not in mouse B cells. Interestingly, both mouse and human lambda enhancers exhibited strong activity in the fish B cells, while the mouse 3' kappa enhancer did not. This suggests that transcription factors similar to those involved in mammalian lambda expression are present in B cells from teleosts.

Ig heavy chain of the sturgeon Acipenser baeri: cDNA sequence and diversity.

To investigate the gene organization of the IGH locus, and the VH diversity of the Siberian sturgeon, a cDNA library was constructed and screened with VH-specific probes from two holostean fish. Isolated clones were analyzed and domain-specific probes used in rescreening of the library, Southern blot analysis, and northern blots. It was concluded that the Siberian sturgeon has one IGH locus with a translocon type of organization. Two allelic variants of the mu gene were found, with identities ranging from 80 to 100% for the different domains (highest for CH4 and lowest for CH2). Sturgeon CH sequences are most closely related to those of holostean fish. There are three distinct VH families, VHI grouping with mammalian clan III, VHII grouping with the teleost clan, and VHIII grouping with the archaic clan. The variability of the CDR 3 region is substantial, and we identified a number of conserved motifs in the D segment. Further, we deduced that there are at least nine different JH segments in the locus, contributing to the antibody repertoire of the sturgeon. The variable segments of the three families can be associated with any of the D or JH segments in the rearrangement. Sturgeon, in addition to the random rearrangement of VH, D, and JH segments, have exonuclease activity, and an introduction of N and probably P nucleotides at the site of rearrangement.

Expression profile of vascular cell adhesion molecule-1 (CD106) in inflammatory foci using rhenium-188 labelled monoclonal antibody in mice.

Rhenium (Re)-188 is a generator (W-188/Re-188) produced high energy beta-emitter suitable for radionuclide therapy (T1/2 is 16.9 hrs and Emax 2.1 MeV (range 11 mm)). We have labelled monoclonal antibody (MAb) raised against vascular cell adhesion molecule-1 (VCAM-1) with Re-188 using glucoheptonate chelation technique and SnCl2 as reducing agent. The labelling efficiency, free perrhenate and reduced Re were controlled with thin layer chromatography and the purification of Re-188-MoAbs was performed using gel filtration. Our results indicate that Re-188-labelled antibodies remain in vitro stable and the labelling purity is > 90%. We also have applied these Re-188-MoAbs for detection of inflammatory disease in a mouse. The effective half-lives of organs of interest after an injection of Re-188-anti-VCAM1 were as follows: blood 5.2 hr, kidney 4.7 hr, and liver 9.6 hr. Re-188-anti-VCAM-1 was found to accumulate mainly in kidney and liver. One hour after the injection, the kidney contained in average as high as 12.5% and the liver 2.8 ID/g tissue. After 6 hr, the kidney contained 5.5% ID/g and the liver 2.6% ID/g. At 24 hr, the kidney uptake was 0.5% ID/g and the liver uptake 0.8% ID/g, respectively. The inflamed foci, subcutaneous lesions in the footpad skin, were visualized using gamma camera. From the distribution data the uptakes in the inflamed foci as follows: at 1 hr 2.18 (inflammation) and 1.72% ID/g (control), at 6 hr 1.42 (inflammation) and 0.85% ID/g (control), and at 24 hr 0.17 (inflammation) and 0.084% ID/g (control), respectively. Anti-VCAM-1 MAb showed better targeting as compared to control MoAbs in inflammation (caused by E.coli lipoplysaccaride). In conclusion, Re-188 is suitable for MAb labelling, and MAb against VCAM-1 may be used for detection of local inflammatory disease.

Pituitary autoantibodies in patients with hypopituitarism and their relatives.

Autoantibodies to human pituitary cytosol proteins were determined by immunoblotting in sera from patients with hypopituitarism and their relatives. Reactivity to an M(r) 49,000 protein was significantly more frequent in patients (6/21 (28%) P < 0.05) as well as in relatives (10/35 (28%) P < 0.02) compared with controls (3/44 (6.8%)). Autoantibodies to this particular protein have previously been detected in sera from 70% of patients with biopsy-proven lymphocytic hypophysitis. Unlike patients with biopsy-proven lymphocytic hypophysitis, none of the patients in this study presented with a suspected pituitary adenoma or showed an enlarged sella turcica. Cisternal herniation was seen in 6/21 patients and this may very well represent the end stage of lymphocytic hypophysitis. Since organ specific autoantibodies are frequent in patients with autoimmune endocrine disease as well as in their unaffected relatives, autoantibodies to this M(r) 49,000 pituitary cytosolic protein may represent markers for an immunological process affecting the pituitary gland.

Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure.Implications for use as a biomarker.

T he association between exposure intensity and serum levels of immunoglobulins E and G against low molecular weight compounds was evaluated. The decay of levels of specific IgE and IgG antibodies was studied after cessation of exposure in workers exposed to the inhalant allergen methyltetrahydrophthalic anhydride in a plant using epoxy resins. Sera have been collected in workers for 18-84 (mean value 54) months after cessation of exposure. Specific IgE and IgG was assessed by RAST and ELISA, respectively. The mean of individual half-times for IgE (N = 10) and IgG (N = 8) was 0 9 (range 0 1-1 8) and 0 4 (range 0 2-0 6) years, respectively, after total avoidance of exposure. Corresponding decreases of IgE and IgG were also observed after reduction, but not total elimination, of exposure. No correlation was seen between biologic halftimes of specific IgE and total IgE, atopy, smoking habits or gender. The results indicate that the levels of specific antibodies in sensitized individuals reflect long term exposure, and may persist for years after the end of exposure.

Antibody response to Arcanobacterium haemolyticum infection in humans.

Arcanobacterium haemolyticum causes pharyngitis, exanthema, and other infections. The evidence of the pathogenicity of A. haemolyticum depends on clinical descriptions of culture-positive patients and a comparison of carrier rates of patients with pharyngitis and healthy, matched controls. In this investigation, the antibody response of the host was studied for the first time, using SDS-PAGE and Western blot analyses. Paired acute and convalescent sera showed development of antibodies to A. haemolyticum in 7 of 8 patients. The antibodies reacted primarily with four distinct cell wall-associated proteins with estimated molecular masses of 80, 60, 50, and 30 kDa. Moreover, the reactivity of convalescent sera from 19 patients was compared with that of sera from 19 controls. Antibodies to A. haemolyticum were found in sera from 16 patients and 6 controls (P < .005); the antibody response of the patients was strong compared with that of the controls. These results indicate that A. haemolyticum infection induces an antibody response in the host.

Lung distension and carbon dioxide affect pulmonary nitric oxide formation in the anaesthetized rabbit.

Positive end-exspiratory pressure (PEEP) and nitric oxide (NO) can influence lung VA/Q-matching and pulmonary vascular resistance, and application of PEEP can increase exhaled NO in animals. To obtain a better understanding of these mechanisms, we examined how different types of ventilation or changes in CO2 affect the formation of endogenous NO. Exhaled NO in pentobarbital-anaesthetized rabbits was monitored by chemiluminescence. The animals were enclosed in a chamber and subjected to various modes of positive as well as negative pressure ventilation which was adjusted to induce similar changes in functional residual capacity (FRC) with maintained ventilatory rate and tidal volume. In addition, stepwise increase in FiCO2 (1.0-10%) was studied. Negative extrathoracic end-exspiratory pressure during negative extrathoracic pressure ventilation produced an increase in NO production similar to that of positive end-exspiratory pressure during positive pressure ventilation, the increase consisting of an initial peak followed by a plateau. The faster the FRC was increased, the higher was the initial peak in NO. The greater the increase in FRC, the higher was the plateau NO concentration. Increased FiCO2 caused a dose-dependent reduction in exhaled NO. The observations of lung distension effects on exhaled NO suggest the possibility of stretch receptors or -receptive mechanisms coupled to NO formation within the lung. In addition, NO formation in the lung is influenced by CO2 in a reciprocal fashion.

Matrix-assisted laser desorption/ionization mass spectrometry of proteins extracted directly from sodium dodecyl sulphate-polyacrylamide gels.

A new strategy for the characterization of Coomassie Brilliant Blue stained SDS-PAGE separated proteins by UV-MALDI-MS is reported. The proteins are extracted directly from the polyacrylamide gel by treatment with an organic solvent mixture consisting of formic acid, acetonitrile, isopropanol and water in an ultrasonic bath. A fraction of the supernatant is then mixed directly with the matrix solution and measured by MALDI-MS. High quality spectra could be obtained from gels which were loaded with 6 pmol of myoglobin. Compared to other methods based on electroblotting or electroelution this method is much simpler and less time consuming. The sensitivity is higher than or comparable to the Coomassie Blue staining procedure for proteins up to about 25 kDa. Another advantage is that mass shifts due to charging effects of the membranes, which are common if membranes are mounted directly on the sample target, can be avoided. However, all proteins studied showed slightly higher masses than expected which reduces mass accuracy to 0.2-0.3%. This is presumably partly due to formylation of serine or threonine residues during incubation in formic acid. Gel electrophoresis induced modifications can contribute as well. The possibility of further characterizing the remaining part of the supernatant after extraction by means of proteolytic digestion is also demonstrated. The knowledge of both molecular weight of the whole protein and of the proteolytic fragments increases specificity for protein identification by searching in sequence databases.

Ig light chain gene in the Siberian sturgeon (Acipenser baeri).

Elasmobranch and teleost fish have their Ig light (L) chain loci organized in multiple clusters (VL-JL-CL). The VL segments of teleosts are in opposite transcriptional orientation to the CL genes, suggesting that in teleosts and elasmobranchs there may have been separate evolutionary events leading to this organization. To address this problem, the IgL locus from the Siberian sturgeon (Acipenser baeri) (representative of a branch between elasmobranchs and teleosts) was investigated. Sequence analysis of cDNA clones shows that sturgeon VL genes are most similar to those of teleosts, but that sturgeon CL genes are more similar to those of the sharks. Southern blot analyses of sturgeon erythrocyte DNA with VL- and CL-specific probes showed that there are more than 20 VL segments in both the tetraploid Siberian sturgeon and the diploid sterlet (Acipenser ruthenus), but only a few CL segments in the genome of the Siberian sturgeon and up to four CL segments in that of the sterlet. Screening of an unamplified genomic library gave more than 300 VL-positive and four CL-positive clones. None of these contained inserts positive for both probes. PCR analysis of a genomic CL clone using IC and CL-specific primers suggested that upstream of the CL segment there are at least seven JL segments. it is concluded that sturgeons have a kappa-like organization of their IgL locus and that the clustered organization of IgL loci in bony fish and sharks arose from two distinct evolutionary events.

Bioavailability and disposition of terodiline in man.

Terodiline was concomitantly administered intravenously (12.5 mg) and orally ([2H]terodiline, 12.5 mg) to 10 healthy volunteers. In four of the subjects, a tracer dose of the intravenously given terodiline was 3H-labeled. In a separate study, six subjects were given [3H]terodiline orally. Estimated pharmacokinetic parameters were as follows: systemic clearance, 93 mL/min; renal clearance, 14 mL/min; volume of distribution at steady-state, 407 L; terminal half-life, 54 h; and mean residence time, 77 h. After intravenous infusion, a rapid distribution phase (half-life, 4.5 min) could be observed. The maximum serum concentration after the oral dose was 29 micrograms/L and the time to maximum concentration was 5 h (estimated by noncompartmental analysis). Absorption commenced within the first hour and by deconvolution the maximum rate of absorption was determined to occur between 1 and 3 h, and by 3.4 h 90% of the available dose had been absorbed. Calculation of bioavailability by noncompartmental AUC, two-compartmental analysis, urinary excretion, and 24-h oral/intravenous concentration ratio gave similar results (ANOVA test, not significant). About 75% and 25% of administered radioactivity could be recovered in urine and feces, respectively. Intact terodiline in feces accounted for about 1% of the dose. p-Hydroxyterodiline was quantitated in feces and accounted for about 5% of the dose. Another metabolite, 3,4-dihydroxyterodiline, which has not previously been detected in urine or serum, was also identified.