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1.  Mortality and molecular epidemiology associated with extended-spectrum β-lactamase production in Escherichia coli from bloodstream infection 
The rate of infections due to extended-spectrum β-lactamase (ESBL)-producing Escherichia coli is growing worldwide. These infections are suspected to be related to increased mortality. We aimed to estimate the difference in mortality due to bloodstream infections (BSIs) with ESBL-positive and ESBL-negative E. coli isolates and to determine the molecular epidemiology of our ESBL-positive isolates.
Materials and methods
We performed a cohort study on consecutive patients with E. coli BSI between 2008 and 2010 at the Charité University Hospital. Collected data were ESBL production, basic demographic parameters, and underlying diseases by the Charlson comorbidity index (CCI). The presence of ESBL genes was analyzed by polymerase chain reaction (PCR) and sequencing. Phylogenetic groups of ESBL-positive E. coli were determined by PCR. Risk factors for mortality were analyzed by multivariable regression analysis.
We identified 115 patients with BSI due to E. coli with ESBL phenotype and 983 due to ESBL-negative E. coli. Fifty-eight percent (n=67) of the ESBL-positive BSIs were hospital-acquired. Among the 99 isolates that were available for PCR screening and sequencing, we found mainly 87 CTX-M producers, with CTX-M-15 (n=55) and CTX-M-1 (n=21) as the most common types. Parameters significantly associated with mortality were age, CCI, and length of stay before and after onset of BSI.
The most common ESBL genotypes in clinical isolates from E. coli BSIs were CTX-M-15 (58%) and CTX-M-1 (22%). ESBL production in clinical E. coli BSI isolates was not related to increased mortality. However, the common occurrence of hospital-acquired BSI due to ESBL-positive E. coli indicates future challenges for hospitals.
PMCID: PMC3958498  PMID: 24648746
BSI; mortality; ESBL-genotype; sepsis
2.  Dimensional Information-Theoretic Measurement of Facial Emotion Expressions in Schizophrenia 
Altered facial expressions of emotions are characteristic impairments in schizophrenia. Ratings of affect have traditionally been limited to clinical rating scales and facial muscle movement analysis, which require extensive training and have limitations based on methodology and ecological validity. To improve reliable assessment of dynamic facial expression changes, we have developed automated measurements of facial emotion expressions based on information-theoretic measures of expressivity of ambiguity and distinctiveness of facial expressions. These measures were examined in matched groups of persons with schizophrenia (n = 28) and healthy controls (n = 26) who underwent video acquisition to assess expressivity of basic emotions (happiness, sadness, anger, fear, and disgust) in evoked conditions. Persons with schizophrenia scored higher on ambiguity, the measure of conditional entropy within the expression of a single emotion, and they scored lower on distinctiveness, the measure of mutual information across expressions of different emotions. The automated measures compared favorably with observer-based ratings. This method can be applied for delineating dynamic emotional expressivity in healthy and clinical populations.
PMCID: PMC3956414  PMID: 24724025
3.  Olfactory processing in schizophrenia, non-ill first-degree family members, and young people at-risk for psychosis 
While deficits in odor identification and discrimination have been reported in schizophrenia, few studies have examined the relative specificity of these deficits in patients and at-risk youth.
Sniffin’ Sticks odor identification and discrimination were assessed in schizophrenia outpatients and non-ill first-degree relatives (Study One), as well as youth at clinical (CR) or genetic (GR) risk for schizophrenia (Study Two). Scores were z-transformed, using the performance of a demographically-matched adult or adolescent comparison group.
Patients and relatives were impaired on odor identification, but odor discrimination impairment was limited to the patient group. A similar pattern of impairment emerged in at-risk youth. GR youth were impaired on odor identification but not discrimination, while CR youth were impaired on both tasks. In patients, olfactory impairment was correlated with negative symptomatology.
To our knowledge, this is the first study to show that CR youth are impaired on both olfactory tasks, as observed in adult schizophrenia patients. GR youth were impaired only on odor identification like their adult counterparts. These data suggest that odor identification impairment, in isolation, may represent a genetic marker of vulnerability for schizophrenia, while odor discrimination deficits may be a biomarker associated with the development of psychosis.
PMCID: PMC3922881  PMID: 22070564
olfaction; smell; prodrome; negative symptoms; psychosis prone
4.  Odor Hedonic Capacity and Anhedonia in Schizophrenia and Unaffected First-Degree Relatives of Schizophrenia Patients 
Schizophrenia Bulletin  2011;39(1):59-67.
Objective: There is increasing evidence that schizophrenia patients have difficulties in the hedonic appraisal of odors. In a prior study, we assessed olfactory hedonic perception birhinally and found that males with schizophrenia failed to attach the appropriate hedonic valence to a pleasant odor, despite correctly perceiving changes in odor intensity. Female patients, in contrast, exhibited normal responses. The current study extends this work by examining odor valence processing in unaffected first-degree relatives of schizophrenia patients, to determine the extent to which this abnormality may be genetically mediated. We also examine odor valence processing unirhinally, rather than birhinally, to probe possible lateralized differences in patients’ hedonic processing deficits. Method: Individuals with schizophrenia (n = 54), first-degree unaffected family members (n = 22), and demographically matched controls (n = 45) were administered the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test. Results: In contrast to family members and controls, both male and female schizophrenia probands underevaluated the hedonic characteristics of amyl acetate at lower concentrations and overevaluated its pleasantness at concentrations perceived as unpleasant by both controls and relatives. These patient-specific differences could not be explained by differences in smoking habit, medication use, or subjective ratings of odor intensity. However, they were associated with increased levels of anhedonia/asociality and negative symptomatology. Conclusions: Our findings suggest that both male and female schizophrenia patients have difficulties in the unirhinal appraisal of hedonic valence. Normal responses in unaffected first-degree relatives suggest that this is an environmentally, rather than genetically, mediated abnormality denoting negative symptomatology.
PMCID: PMC3523921  PMID: 21616912
smell; olfactory; valence processing; pleasantness; emotion; olfaction
5.  Different Patterns of Epstein-Barr Virus Latency in Endemic Burkitt Lymphoma (BL) Lead to Distinct Variants within the BL-Associated Gene Expression Signature 
Journal of Virology  2013;87(5):2882-2894.
Epstein-Barr virus (EBV) is present in all cases of endemic Burkitt lymphoma (BL) but in few European/North American sporadic BLs. Gene expression arrays of sporadic tumors have defined a consensus BL profile within which tumors are classifiable as “molecular BL” (mBL). Where endemic BLs fall relative to this profile remains unclear, since they not only carry EBV but also display one of two different forms of virus latency. Here, we use early-passage BL cell lines from different tumors, and BL subclones from a single tumor, to compare EBV-negative cells with EBV-positive cells displaying either classical latency I EBV infection (where EBNA1 is the only EBV antigen expressed from the wild-type EBV genome) or Wp-restricted latency (where an EBNA2 gene-deleted virus genome broadens antigen expression to include the EBNA3A, -3B, and -3C proteins and BHRF1). Expression arrays show that both types of endemic BL fall within the mBL classification. However, while EBV-negative and latency I BLs show overlapping profiles, Wp-restricted BLs form a distinct subgroup, characterized by a detectable downregulation of the germinal center (GC)-associated marker Bcl6 and upregulation of genes marking early plasmacytoid differentiation, notably IRF4 and BLIMP1. Importantly, these same changes can be induced in EBV-negative or latency I BL cells by infection with an EBNA2-knockout virus. Thus, we infer that the distinct gene profile of Wp-restricted BLs does not reflect differences in the identity of the tumor progenitor cell per se but differences imposed on a common progenitor by broadened EBV gene expression.
PMCID: PMC3571367  PMID: 23269792
6.  An odor-specific threshold deficit implicates abnormal cAMP signaling in youths at clinical risk for psychosis 
Schizophrenia Research  2012;138(2-3):280-284.
While olfactory deficits have been reported in schizophrenia and youths at-risk for psychosis, few studies have linked these deficits to current pathophysiological models of the illness. There is evidence that disrupted cyclic adenosine 3’,5’-monophosphate (cAMP) signaling may contribute to schizophrenia pathology. As cAMP mediates olfactory signal transduction, the degree to which this disruption could manifest in olfactory impairment was ascertained. Odor-detection thresholds to two odorants that differ in the degree to which they activate intracellular cAMP were assessed in clinical risk and low-risk participants.
Birhinal assessments of odor-detection threshold sensitivity to lyral and citralva were acquired in youths experiencing prodromal symptoms (n = 17) and controls at low risk for developing psychosis (n = 15). Citralva and lyral are odorants that differ in cAMP activation; citralva is a strong cAMP activator and lyral is a weak cAMP activator.
The overall group-by-odor interaction was statistically significant. At-risk youths showed significantly reduced odor detection thresholds for lyral, but showed intact detection thresholds for citralva. This odor-specific threshold deficit was uncorrelated with deficits in odor identification or discrimination, which were also present. ROC curve analysis revealed that olfactory performance correctly classified at-risk and low-risk youths with greater than 97% accuracy.
This study extends prior findings of an odor-specific hyposmia implicating cAMP-mediated signal transduction in schizophrenia and unaffected first-degree relatives to include youths at clinical risk for developing the disorder. These results suggest that dysregulation of cAMP signaling may be present during the psychosis prodrome.
PMCID: PMC3372687  PMID: 22537567
schizophrenia prodrome; ultra high risk; cAMP; adenosine cyclase; DISC1
7.  A Meta-Analysis of Emotion Perception and Functional Outcomes in Schizophrenia 
Schizophrenia Research  2012;137(1-3):203-211.
Emotion perception (EP) is impaired in schizophrenia, is stable across clinical state, resistant to antipsychotic treatment and linked to symptom severity. Given its pervasive nature, there is a need to quantitatively examine whether this dysfunction impacts functional outcomes. We used a meta-analytic strategy to combine results from several studies and examine synthesized effect sizes.
A Meta-analysis Of Observational Studies in Epidemiology standard was used to extract data following a PubMed and PsychInfo search. Studies reporting correlations between measures of EP and functional outcomes in schizophrenia spectrum disorders were selected. The impact of potential methodological (task type), demographic (sex, age, race, education, marital status) and clinical (age of onset, duration of illness, setting, symptoms, anti-psychotic medication) moderators on effect sizes were examined.
Twenty-five studies met inclusion criteria and included 1306 patients who were 37 years old, with 12 years of education, 64% male and 63% Caucasian. There was a significant relationship between EP and functional outcomes in individuals with schizophrenia or schizoaffective disorder, with effect sizes in the medium range. Medium to large range positive correlations were observed between emotion identification and functional outcome domains involving social problem solving, social skills and community functioning. Significant moderators included task type (emotion identification tasks), sex (% male in sample), race (% Caucasian in sample) and clinical symptoms (negative and positive).
Emotion identification deficits are associated with functional impairments in schizophrenia and moderated by sex, race and symptoms. This has implications for treatment efforts to improve outcomes.
PMCID: PMC3351501  PMID: 22341200
emotion perception; social cognition; schizophrenia; functional outcome; quality of life; meta-analysis
8.  Evaluation and Treatment of Children and Adolescents with Psychotic Symptoms 
Current psychiatry reports  2012;14(2):101-110.
In recent years, there have been increasing efforts to develop early detection and prevention strategies for patients at risk of the development of psychotic disorders. These efforts have led to improved recognition and characterization of psychotic symptoms in youth. This review focuses on the evaluation of children and adolescents with psychotic symptoms who are experiencing functional impairment but who do not meet current criteria for schizophrenia. For this article, emphasis is placed on the evaluation of symptoms, differential diagnosis, and consideration of potential interventions.
PMCID: PMC3500659  PMID: 22350543
Ultra high risk (UHR); Prodrome; At-risk; Psychosis; Psychotic symptoms; Children; Adolescents; Schizophrenia; Youth
11.  Computerized Neurocognitive Profile in Young People with 22q11.2 Deletion Syndrome Compared to Youths with Schizophrenia and At-risk for Psychosis 
Adults with 22q11.2 Deletion Syndrome (22q11DS) have increased prevalence of schizophrenia features. Our goal is to compare the neurocognitive profile in 22q11DS, schizophrenia and individuals at risk for schizophrenia.
Twenty-one 22q11DS patients (8y-32y, mean 14.9y, 15M 6F) were matched to four comparison groups on age: low risk (n=21), first-degree family members of schizophrenia patients (genetic risk, n=20), individuals exhibiting putatively prodromal symptoms (clinical risk, n=19), and patients with schizophrenia (n=21). All participants received semi-structured interviews [Diagnostic Interview for Genetic Studies (DIGS) and the Structured Interview for Prodromal Syndromes (SIPS)], and a computerized neurocognitive battery (CNB) measuring the following domains: Abstraction and Mental Flexibility, Attention, Working Memory, Verbal Memory, Face Memory, Spatial Memory, Language, Spatial Processing, Sensorimotor Dexterity, and Emotion Processing.
60% of 22q11DS participants met SIPS criteria for prodromal symptoms and one participant met criteria for paranoid schizophrenia. 38% met criteria for Depressive Disorders. All 22q11DS participants successfully completed the CNB. 22q11DS participants were significantly less accurate in nearly all domains, but had similar speed of response compared to the other groups. Their profile resembled that of the psychosis groups in accuracy and speed, except for more pronounced deficits in accuracy for face memory and emotion processing.
Subthreshold psychotic symptoms are present in a high proportion of 22q11DS participants. Deficits shown in the CNB are more pronounced for accuracy than speed relative to the psychosis groups with similar profiles. Similar deficits have been described in the 22q11DS population using non-computerized measures, which require increased testing time.
PMCID: PMC3272485  PMID: 22170773
22q11.2 Deletion Syndrome; VCFS; schizophrenia risk; neuropsychology
12.  SOCS1 Mutation Subtypes Predict Divergent Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) Patients 
Oncotarget  2012;4(1):35-47.
Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL.
PMCID: PMC3702206  PMID: 23296022
Lymphoma; DLBCL; SOCS1 mutation
13.  Extracytoplasmic function (ECF) sigma factor σF is involved in Caulobacter crescentus response to heavy metal stress 
BMC Microbiology  2012;12:210.
The α-proteobacterium Caulobacter crescentus inhabits low-nutrient environments and can tolerate certain levels of heavy metals in these sites. It has been reported that C. crescentus responds to exposure to various heavy metals by altering the expression of a large number of genes.
In this work, we show that the ECF sigma factor σF is one of the regulatory proteins involved in the control of the transcriptional response to chromium and cadmium. Microarray experiments indicate that σF controls eight genes during chromium stress, most of which were previously described as induced by heavy metals. Surprisingly, σF itself is not strongly auto-regulated under metal stress conditions. Interestingly, σF-dependent genes are not induced in the presence of agents that generate reactive oxygen species. Promoter analyses revealed that a conserved σF-dependent sequence is located upstream of all genes of the σF regulon. In addition, we show that the second gene in the sigF operon acts as a negative regulator of σF function, and the encoded protein has been named NrsF (Negative regulator of sigma F). Substitution of two conserved cysteine residues (C131 and C181) in NrsF affects its ability to maintain the expression of σF-dependent genes at basal levels. Furthermore, we show that σF is released into the cytoplasm during chromium stress and in cells carrying point mutations in both conserved cysteines of the protein NrsF.
A possible mechanism for induction of the σF-dependent genes by chromium and cadmium is the inactivation of the putative anti-sigma factor NrsF, leading to the release of σF to bind RNA polymerase core and drive transcription of its regulon.
PMCID: PMC3511200  PMID: 22985357
Stress response; ECF sigma factor σF; Chromium; Cadmium; Caulobacter crescentus
14.  Automated Facial Action Coding System for Dynamic Analysis of Facial Expressions in Neuropsychiatric Disorders 
Journal of Neuroscience Methods  2011;200(2):237-256.
Facial expression is widely used to evaluate emotional impairment in neuropsychiatric disorders. Ekman and Friesen’s Facial Action Coding System (FACS) encodes movements of individual facial muscles from distinct momentary changes in facial appearance. Unlike facial expression ratings based on categorization of expressions into prototypical emotions (happiness, sadness, anger, fear, disgust, etc.), FACS can encode ambiguous and subtle expressions, and therefore is potentially more suitable for analyzing the small differences in facial affect. However, FACS rating requires extensive training, and is time consuming and subjective thus prone to bias. To overcome these limitations, we developed an automated FACS based on advanced computer science technology. The system automatically tracks faces in a video, extracts geometric and texture features, and produces temporal profiles of each facial muscle movement. These profiles are quantified to compute frequencies of single and combined Action Units (AUs) in videos, which can facilitate statistical study of large populations in disorders affecting facial expression. We derived quantitative measures of flat and inappropriate facial affect automatically from temporal AU profiles. Applicability of the automated FACS was illustrated in a pilot study, by applying it to data of videos from eight schizophrenia patients and controls. We created temporal AU profiles that provided rich information on the dynamics of facial muscle movements for each subject. The quantitative measures of flatness and inappropriateness showed clear differences between patients and the controls, highlighting their potential in automatic and objective quantification of symptom severity.
PMCID: PMC3402717  PMID: 21741407
Facial Expressions; Facial Action Coding System; action units; Computerized Method
15.  Actively Paranoid Patients with Schizophrenia Over Attribute Anger to Neutral Faces 
Schizophrenia research  2010;125(2-3):174-178.
Previous investigations of the influence of paranoia on facial affect recognition in schizophrenia have been inconclusive as some studies demonstrate better performance for paranoid relative to non-paranoid patients and others show that paranoid patients display greater impairments. These studies have been limited by small sample sizes and inconsistencies in the criteria used to define groups. Here, we utilized an established emotion recognition task and a large sample to examine differential performance in emotion recognition ability between patients who were actively paranoid (AP) and those who were not actively paranoid (NAP). Accuracy and error patterns on the Penn Emotion Recognition test (ER40) were examined in 132 patients (64 NAP and 68 AP). Groups were defined based on the presence of paranoid ideation at the time of testing rather than diagnostic subtype. AP and NAP patients did not differ in overall task accuracy; however, an emotion by group interaction indicated that AP patients were significantly worse than NAP patients at correctly labeling neutral faces. A comparison of error patterns on neutral stimuli revealed that the groups differed only in misattributions of anger expressions, with AP patients being significantly more likely to misidentify a neutral expression as angry. The present findings suggest that paranoia is associated with a tendency to over attribute threat to ambiguous stimuli and also lend support to emerging hypotheses of amygdala hyperactivation as a potential neural mechanism for paranoid ideation.
PMCID: PMC3031724  PMID: 21112186
Paranoia; facial emotion recognition; amygdala; social cognition
16.  Ventrolateral prefrontal cortex and the effects of task demand context on facial affect appraisal in schizophrenia 
Schizophrenia patients display impaired performance and brain activity during facial affect recognition. These impairments may reflect stimulus-driven perceptual decrements and evaluative processing abnormalities. We differentiated these two processes by contrasting responses to identical stimuli presented under different contexts. Seventeen healthy controls and 16 schizophrenia patients performed an fMRI facial affect detection task. Subjects identified an affective target presented amongst foils of differing emotions. We hypothesized that targeting affiliative emotions (happiness, sadness) would create a task demand context distinct from that generated when targeting threat emotions (anger, fear). We compared affiliative foil stimuli within a congruent affiliative context with identical stimuli presented in an incongruent threat context. Threat foils were analysed in the same manner. Controls activated right orbitofrontal cortex (OFC)/ventrolateral prefrontal cortex (VLPFC) more to affiliative foils in threat contexts than to identical stimuli within affiliative contexts. Patients displayed reduced OFC/VLPFC activation to all foils, and no activation modulation by context. This lack of context modulation coincided with a 2-fold decrement in foil detection efficiency. Task demands produce contextual effects during facial affective processing in regions activated during affect evaluation. In schizophrenia, reduced modulation of OFC/VLPFC by context coupled with reduced behavioural efficiency suggests impaired ventral prefrontal control mechanisms that optimize affective appraisal.
PMCID: PMC3023083  PMID: 20212004
schizophrenia; social cognition; face; emotion; amygdala; ventrolateral prefrontal cortex (VLPFC); orbitofrontal cortex (OFC); fMRI
17.  Facial Emotion Perception in Schizophrenia: A Meta-analytic Review 
Schizophrenia Bulletin  2009;36(5):1009-1019.
Objectives: A considerable body of literature has reported on emotion perception deficits and the relevance to clinical symptoms and social functioning in schizophrenia. Studies published between 1970–2007 were examined regarding emotion perception abilities between patient and control groups and potential methodological, demographic, and clinical moderators. Data Sources and Review: Eighty-six studies were identified through a computerized literature search of the MEDLINE, PsychINFO, and PubMed databases. A quality of reporting of meta-analysis standard was followed in the extraction of relevant studies and data. Data on emotion perception, methodology, demographic and clinical characteristics, and antipsychotic medication status were compiled and analyzed using Comprehensive Meta-analysis Version 2.0 (Borenstein M, Hedges L, Higgins J and Rothstein H. Comprehensive Meta-analysis. 2. Englewood, NJ: Biostat; 2005). Results: The meta-analysis revealed a large deficit in emotion perception in schizophrenia, irrespective of task type, and several factors that moderated the observed impairment. Illness-related factors included current hospitalization and—in part—clinical symptoms and antipsychotic treatment. Demographic factors included patient age and gender in controls but not race. Conclusion: Emotion perception impairment in schizophrenia represents a robust finding in schizophrenia that appears to be moderated by certain clinical and demographic factors. Future directions for research on emotion perception are discussed.
PMCID: PMC2930336  PMID: 19329561
schizophrenia; meta-analysis; emotion perception
18.  Dynamic evoked facial expressions of emotions in schizophrenia 
Schizophrenia research  2008;105(1-3):30-39.
Impaired facial expressions of emotions have been described as characteristic symptoms of schizophrenia. Previous investigations of dynamic facial expressions have reported on global assessment of positive and negative emotion expressions. In this study, we examined facial expression differences based on duration and frequencies of emotion expressions.
12 persons with stable schizophrenia and matched healthy controls underwent a standardized procedure for evoked facial expressions of five universal emotions, including happy, sad, anger, fear, and disgust expressions. Subjects completed self-ratings of their emotion experience. Reliable raters coded evoked facial expressions according to the Facial Expression Coding System. For each emotion, facial expressions were coded as target, non-target or neutral expressions. Logistic regression analyses examined group differences in duration and frequencies of facial expressions.
Comparing overall duration of and frequencies of emotion expressions revealed affective flattening and inappropriate affect in patients, as evidenced by neutral and non-target expressions. Separated by emotion, impaired emotion expression was found in happy, sad and anger expression, but not for fear and disgust in which expressions were not well recognized.
In matched groups of participants, we found evidence for altered expressions in schizophrenia but equal subjective experience. Both affective flattening and inappropriate affect comprise abnormal facial expressions but may differ with respect to interpersonal communication and engagement. Future directions may include automated measurement, remediation of expressions and early detection of schizophrenia.
PMCID: PMC2879330  PMID: 18793827
Dynamic emotion expression; Schizophrenia; Facial Expression Coding System; Affective flattening; Inappropriate affect
19.  The profile of auditory information processing deficits in schizophrenia 
Psychiatry research  2008;165(1-2):27-37.
Schizophrenia patients exhibit abnormalities in several different auditory ERP measures. It is unclear how these abnormalities relate to each other, since multiple measures are rarely acquired from the same sample. This study addressed two related questions: 1)Are specific auditory ERP measures differentially impaired in schizophrenia? 2)Do abnormalities co-aggregate within the same patients? Nine auditory ERP measures were acquired in a single testing session from 23 schizophrenia patients and 22 healthy subjects. Hierarchical oblique factor analysis revealed that these measures aggregated into 4 factors, with each loading primarily on a single factor. Patient deficits were observed for two independent factors: N100/MMN and P3a/P3b. N100/MMN abnormalities were associated with symptoms of alogia and formal thought disorder. P3a/P3b abnormalities were associated with avolition, attentional disturbances and delusions. We conclude that deficits in different ERP measures of early sensory processing at the level of the auditory cortex co-occur in patients. These likely represent a single differential deficit indexing the physiological abnormality underlying impaired language and verbal processing. This is relatively independent of a higher cortical deficit that mediates cognitive stimulus evaluation and underlies deficits in motivation, attention and reality testing. Such multidimensional profiling of ERP abnormalities may help to clarify the clinical and genetic heterogeneity of schizophrenia.
PMCID: PMC2652872  PMID: 18990453
evoked potentials; schizophrenia; P50; PPI; N100; mismatch negativity; P300
20.  Abnormal Superior Temporal Connectivity During Fear Perception in Schizophrenia 
Schizophrenia Bulletin  2008;34(4):673-678.
Patients with schizophrenia have difficulty in decoding facial affect. A study using event–related functional neuroimaging indicated that errors in fear detection in schizophrenia are associated with paradoxically higher activation in the amygdala and an associated network implicated in threat detection. Furthermore, this exaggerated activation to fearful faces correlated with severity of flat affect. These findings suggest that abnormal threat detection processing may reflect disruptions between nodes that comprise the affective appraisal circuit. Here we examined connectivity within this network by determining the pattern of intercorrelations among brain regions (regions of interest) significantly activated during fear identification in both healthy controls and patients using a novel procedure CORANOVA. This analysis tests differences in the interregional correlation strength between schizophrenia and healthy controls. Healthy subjects' task activation was principally characterized by robust correlations between medial structures like thalamus (THA) and amygdala (AMY) and middle frontal (MF), inferior frontal (IF), and prefrontal cortical (PFC) regions. In contrast, schizophrenia patients displayed no significant correlations between the medial regions and either MF or IF. Further, patients had significantly higher correlations between occipital lingual gyrus and superior temporal gyrus than healthy subjects. These between-group connectivity differences suggest that schizophrenia threat detection impairment may stem from abnormal stimulus integration. Such abnormal integration may disrupt the evaluation of threat within fronto-cortical regions.
PMCID: PMC2632445  PMID: 18550592
schizophrenia; social cognition; face; emotion; amygdala; fMRI
21.  Olfactory Physiological Impairment in First-Degree Relatives of Schizophrenia Patients 
Schizophrenia research  2008;102(1-3):220-229.
Efforts to characterize genetic vulnerability to schizophrenia are increasingly focused on the identification of endophenotypes - neurobiological abnormalities that are evident in individuals at risk. Behavioral studies have demonstrated olfactory impairments in odor detection and identification in unaffected 1st-degree relatives of schizophrenia patients, suggesting that abnormalities in this simple sensory system may serve as candidate endophenotypes. It is unclear, however, whether these behavioral abnormalities reflect basic olfactory sensory processing deficits or nonspecific disruptions of attention and cognition.
Unirhinal chemosensory olfactory evoked potentials were acquired from 14 unaffected 1st-degree relatives of schizophrenia patients and 20 healthy individuals with equivalent age and gender distributions, using 3 different concentrations of hydrogen sulfide. Subjects were also assessed behaviorally for ability to detect and identify odors.
Family members exhibited left nostril olfactory detection impairments and bilateral olfactory identification abnormalities. They had reduced evoked potential response amplitudes for the initial N1 component in the left nostril. The subsequent P2 evoked potential response was reduced bilaterally. The pattern and magnitude of family member deficits were comparable to those previously observed for schizophrenia patients.
1st-degree relatives of schizophrenia patients exhibit specific neurophysiological impairments in early olfactory sensory processing. The presence of these neurophysiological abnormalities in both schizophrenia patients and their unaffected 1st-degree relatives suggests that these represent genetically mediated vulnerability markers or endophenotypes of the illness.
PMCID: PMC2504534  PMID: 18457935
schizophrenia; olfaction; endophenotype; evoked potentials; genetic vulnerability
22.  Reduced Posterior Nasal Cavity Volume: A Gender-Specific Neurodevelopmental Abnormality in Schizophrenia 
Schizophrenia research  2007;93(1-3):237-244.
We previously reported that men with schizophrenia had reduced volumes of the posterior nasal cavity bilaterally. Since the nasal cavities develop in conjunction with both the palate and ventral forebrain, this could represent a simple marker of embryological dysmorphogenesis contributing to schizophrenia. The current study expands on this finding by examining a larger sample of both male and female patients and unaffected 1st-degree relatives, to determine the gender distribution of this abnormality and the extent to which it may be genetically mediated.
A measurement of nasal volume and geometry was acquired by acoustic rhinometry for 85 schizophrenia patients, 25 unaffected first-degree relatives of schizophrenia probands and 66 healthy comparison subjects.
Male patients had smaller posterior nasal volumes than both male control subjects and male relatives. However, female patients did not differ from either female controls or female family members. Unaffected first-degree relatives did not differ from same-sex control subjects. These findings persisted after covarying for height and smoking history, and were unrelated to clinical symptomatology or antipsychotic medication usage.
Posterior nasal cavity volume decrement appears to be a specific developmental craniofacial abnormality that may reflect an early disruption in embryological development in males with schizophrenia. Although further study is needed, this may be a marker of a “second hit” that distinguishes genetically vulnerable men who go on to develop the illness from those who do not.
PMCID: PMC2692622  PMID: 17433628
schizophrenia; nasal volume; neurodevelopment; embryogenesis; genetic vulnerability
23.  Computerized Measurement of Facial Expression of Emotions in Schizophrenia 
Journal of neuroscience methods  2007;163(2):350-361.
Deficits in the ability to express emotions characterize several neuropsychiatric disorders and are a hallmark of schizophrenia, and there is need for a method of quantifying expression, which is currently done by clinical ratings. This paper presents the development and validation of a computational framework for quantifying emotional expression differences between patients with schizophrenia and healthy controls. Each face is modeled as a combination of elastic regions, and expression changes are modeled as a deformation between a neutral face and an expressive face. Functions of these deformations, known as the regional volumetric difference (RVD) functions, form distinctive quantitative profiles of expressions. Employing pattern classification techniques, we have designed expression classifiers for the four universal emotions of happiness, sadness, anger and fear by training on RVD functions of expression changes. The classifiers were cross validated and then applied to facial expression images of patients with schizophrenia and healthy controls. The classification score for each image reflects the extent to which the expressed emotion matches the intended emotion. Group-wise statistical analysis revealed this score to be significantly different between healthy controls and patients, especially in the case of anger. This score correlated with clinical severity of flat affect. These results encourage the use of such deformation based expression quantification measures for research in clinical applications that require the automated measurement of facial affect.
PMCID: PMC2692190  PMID: 17442398
24.  Evaluation of the passage of Lactobacillus gasseri K7 and bifidobacteria from the stomach to intestines using a single reactor model 
BMC Microbiology  2009;9:87.
Probiotic bacteria are thought to play an important role in the digestive system and therefore have to survive the passage from stomach to intestines. Recently, a novel approach to simulate the passage from stomach to intestines in a single bioreactor was developed. The advantage of this automated one reactor system was the ability to test the influence of acid, bile salts and pancreatin.
Lactobacillus gasseri K7 is a strain isolated from infant faeces with properties making the strain interesting for cheese production. In this study, a single reactor system was used to evaluate the survival of L. gasseri K7 and selected bifidobacteria from our collection through the stomach-intestine passage.
Initial screening for acid resistance in acidified culture media showed a low tolerance of Bifidobacterium dentium for this condition indicating low survival in the passage. Similar results were achieved with B. longum subsp. infantis whereas B. animalis subsp. lactis had a high survival.
These initial results were confirmed in the bioreactor model of the stomach-intestine passage. B. animalis subsp. lactis had the highest survival rate (10%) attaining approximately 5 × 106 cfu ml-1 compared to the other tested bifidobacteria strains which were reduced by a factor of up to 106. Lactobacillus gasseri K7 was less resistant than B. animalis subsp. lactis but survived at cell concentrations approximately 1000 times higher than other bifidobacteria.
In this study, we were able to show that L. gasseri K7 had a high survival rate in the stomach-intestine passage. By comparing the results with a previous study in piglets we could confirm the reliability of our simulation. Of the tested bifidobacteria strains, only B. animalis subsp. lactis showed acceptable survival for a successful passage in the simulation system.
PMCID: PMC2685402  PMID: 19426473
25.  A Defect in Menadione Biosynthesis Induces Global Changes in Gene Expression in Staphylococcus aureus▿ †  
Journal of Bacteriology  2008;190(19):6351-6364.
Both the high-resolution two-dimensional protein gel electrophoresis technique and full-genome DNA microarrays were used for identification of Staphylococcus aureus genes whose expression was changed by a mutation in menD. Because the electron transport chain is interrupted, the mutant should be unable to use oxygen and nitrate as terminal electron acceptors. Consistent with this, a mutation in menD was found to cause a gene expression pattern typically detected under anaerobic conditions in wild-type cells: proteins involved in glycolytic as well as in fermentation pathways were upregulated, whereas tricarboxylic acid (TCA) cycle enzymes were significantly downregulated. Moreover, the expression of genes encoding enzymes for nitrate respiration and the arginine deiminase pathway was strongly increased in the mutant strain. These results indicate that the menD mutant, just as the site-directed S. aureus hemB mutant, generates ATP from glucose or fructose mainly by substrate phosphorylation and might be defective in utilizing a variety of carbon sources, including TCA cycle intermediates and compounds that generate ATP only via electron transport phosphorylation. Of particular interest is that there are also differences in the gene expression patterns between hemB and menD mutants. While some anaerobically active enzymes were present in equal amounts in both strains (Ldh1, SACOL2535), other classically anaerobic enzymes seem to be present in higher amounts either in the hemB mutant (e.g., PflB, Ald1, IlvA1) or in the menD mutant (arc operon). Only genes involved in nitrate respiration and the ald1 operon seem to be additionally regulated by a depletion of oxygen in the hemB and/or menD mutant.
PMCID: PMC2566006  PMID: 18676673

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