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Background: Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release., Methods: Patients with SCZ ( n  = 41) and healthy control participants (HCs) ( n  = 40) performed a visual object n-back task during functional magnetic resonance imaging. Dopamine release capacity in mPFC was quantified with [ 11 C]FLB457 in a subset of participants (9 SCZ, 14 HCs) using an amphetamine challenge. Correlations between task-evoked deactivation and performance were assessed in mPFC and dorsolateral PFC masks and were further examined for relationships with diagnosis and dopamine release., Results: mPFC deactivation was associated with WM task performance, but dorsolateral PFC activation was not. Deactivation in the mPFC was reduced in patients with SCZ relative to HCs and mediated the relationship between diagnosis and WM performance. In addition, mPFC deactivation was significantly and inversely associated with dopamine release capacity across groups and in HCs alone, but not in patients., Conclusions: Reduced WM task-evoked mPFC deactivation is a mediator of, and potential substrate for, WM impairment in SCZ, although our study design does not rule out the possibility that these findings could relate to cognition in general rather than WM specifically. We further present preliminary evidence of an inverse association between deactivation during WM tasks and dopamine release capacity in the mPFC., (© 2022 The Authors.)

Background: Chronic kidney disease (CKD) is a recognized global health problem. While some CKD patients remain stable after initial diagnosis, others can rapidly progress towards end-stage renal disease (ESRD). This makes biomarkers capable of detecting progressive forms of CKD extremely valuable, especially in non-invasive biofluids such as urine. Screening for metabolite markers using non-targeted metabolomic techniques like nuclear magnetic resonance spectroscopy is increasingly applied to CKD research., Methods: A cohort of CKD patients (n = 227) with estimated glomerular filtration rates (eGFRs) ranging from 9.4-130 mL/min/1.73 m2 was evaluated and urine metabolite profiles were characterized in relation to declining eGFR. Nested in this cohort, a retrospective subset (n = 57) was investigated for prognostic metabolite markers of CKD progression, independent of baseline eGFR. A transcriptomic analysis of murine models of renal failure was performed to validate selected metabolomic findings., Results: General linear modeling revealed 11 urinary metabolites with significant associations to reduced eGFR. Linear modelling specifically showed that increased urine concentrations of betaine (P < 0.05) and myo-inositol (P < 0.05) are significant prognostic markers of CKD progression., Conclusions: Renal organic osmolytes, betaine and myo-inositol play a critical role in protecting renal cells from hyperosmotic stress. Kidney tissue transcriptomics of murine preclinical experimentation identified decreased expression of Slc6a12 and Slc5a11 mRNA in renal tissue consistent with defective tubular transport of these osmolytes. Imbalances in renal osmolyte regulation lead to increased renal cell damage and thus more progressive forms of CKD. Increases in renal osmolytes in urine could provide clinical diagnostic and prognostic information on CKD outcomes.

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [ 11 C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg -1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BP ND ) and derived percent reduction from baseline (ΔBP ND ) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BP ND to baseline differed between SZ and HCs, we implemented a linear model with ΔBP ND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBP ND (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BP ND to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

Acute kidney injury (AKI) is a severe and frequent condition in hospitalized patients. Currently, no efficient therapy of AKI is available. Therefore, efforts focus on early prevention and potentially early initiation of renal replacement therapy to improve the outcome in AKI. The detection of AKI in hospitalized patients implies the need for early, accurate, robust, and easily accessible biomarkers of AKI evolution and outcome prediction because only a narrow window exists to implement the earlier-described measures. Even more challenging is the multifactorial origin of AKI and the fact that the changes of molecular expression induced by AKI are difficult to distinguish from those of the diseases associated or causing AKI as shock or sepsis. During the past decade, a considerable number of protein biomarkers for AKI have been described and we expect from recent advances in the field of omics technologies that this number will increase further in the future and be extended to other sorts of biomolecules, such as RNAs, lipids, and metabolites. However, most of these biomarkers are poorly defined by their AKI-associated molecular context. In this review, we describe the state-of-the-art tissue and biofluid proteomic and metabolomic technologies and new bioinformatics approaches for proteomic and metabolomic pathway and molecular interaction analysis. In the second part of the review, we focus on AKI-associated proteomic and metabolomic biomarkers and briefly outline their pathophysiological context in AKI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The oxygenation of Champagne wine after 4 and 6 years of aging on lees in bottle was investigated by FTICR-MS and UPLC-Q-TOF-MS. Three levels of permeability were considered for the stoppers, ranging from 0.2 to 1.8 mg/L/year of oxygen transfer rate. Our results confirmed a good repeatability of ultra-high resolution FTICR-MS, both in terms of m/z and coefficient of variation of peak intensities among biological replicates. Vintages appeared to be the most discriminated features, and metabolite annotations suggested that the oldest wines (2006) were characterized by a higher sensitivity towards oxygenation. Within each vintage, the oxygenation mechanisms appeared to be different for low and high ingresses of oxygen, in agreement with the hormesis character of wine oxygenation. In the particular case of single variety wines and for a given level of stopper permeability, our results also showed that variety discrimination could be easily achieved among wines., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Metabolite profiling of urine has seen much advancement in recent years, and its analysis by nuclear magnetic resonance (NMR) spectroscopy has become well established. However, the highly variable nature of human urine still requires improved protocols despite some standardization. In particular, diseases such as kidney disease can have a profound effect on the composition of urine and generate a highly diverse sample set for clinical studies. Large variations in pH and the cationic concentration of urine play an important role in creating positional noise within datasets generated from NMR. We demonstrate positional noise to be a confounding variable for multivariate statistical tools such as statistical total correlation spectroscopy (STOCSY), thereby hindering the process of biomarker discovery. We present a two-dimensional buffering system using potassium fluoride (KF) and phosphate buffer to reduce positional noise in metabolomic data generated from urine samples with various levels of proteinuria. KF reduces positional noise in citrate peaks, by decreasing the mean relative standard deviation (RSD) from 0.17 to 0.09. By reducing positional noise with KF, STOCSY analysis of citrate peaks saw significant improvement. We further aligned spectral data using a recursive segment-wise peak alignment (RSPA) method, which leads to further improvement of the positional noise (RSD = 0.06). These results were validated using diverse selection of metabolites which lead to an overall improvement in positional noise using the suggested protocol. In summary, we provide an improved workflow for urine metabolite biomarker discovery to achieve higher data quality for better pathophysiological understanding of human diseases. Graphical abstract Citrate peaks in the range 2.75-2.5 ppm from datasets with different sample preparation protocols and with/without in silico alignment. A Citrate peaks with standard phosphate buffering and without in silico alignment. B citrate peaks with standard phosphate buffering and with in silico alignment. C citrate peak with additional potassium fluoride and standard phosphate buffering without in silico alignment. D citrate peaks with additional potassium fluoride and standard phosphate buffering with in silico alignment. Below the respective spectrum are displayed the percent relative standard deviation (RSD) of the respective citrate peaks. This is a measure of the positional noise of peaks within a (1)H NMR analysis. It can be seen that D performs the best in reducing positional noise of citrate peaks. E-H STOCSY analysis of correlating spectral features with the driver peak at 2.675 ppm (see red arrow) to identify structural correlations. As a, b, c, and d are known to be structurally correlated, STOCSY analysis should reveal r (2) = 1 if data is perfectly aligned and can therefore be used as a measure of peak alignment. E Strong positional noise does not allow identifying the c and d peaks of the AB system to be correlated. F, G Neither in silico alignment or KF addition alone can completely improve the alignment and therefore increase the correlations. H Highly improved alignment by combining both KF addition and in silico alignment reduces positional noise and elucidates all four citrate peaks to be strongly correlated.

Background: All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans., Methods: We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND., Results: We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmental area). Using a regression model to estimate D2R:D3R selectivity, we observed a D2R:D3R selectivity of 2.1 for risperidone., Conclusion: Our preliminary results provide further support that acute doses of antipsychotic medications bind to the D3R and provide additional support for the further development of this receptor as a treatment target in schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To analyze the direct cost of reusable and disposable aprons in a public teaching hospital., Method: Cross-sectional study of quantitative approach, focusing on the direct cost of reusable and disposable aprons at a teaching hospital in northern Paraná. The study population consisted of secondary data collected in reports of the cost of services, laundry, materials and supplies division of the institution for the year 2012., Results: We identified a lower average cost of using disposable apron when compared to the reusable apron. The direct cost of reusable apron was R$ 3.06, and the steps of preparation and washing were mainly responsible for the high cost, and disposable apron cost was R$ 0.94., Conclusion: The results presented are important for hospital managers properly allocate resources and manage costs in hospitals
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Rationale: Deterioration of ventricular fibrillation (VF) into asystole or severe bradycardia (electrical failure) heralds a fatal outcome of cardiac arrest. The role of metabolism in the timing of electrical failure remains unknown., Objective: To determine metabolic factors of early electrical failure in an ex-vivo canine model of cardiac arrest (VF+global ischemia)., Methods and Results: Metabolomic screening was performed in left ventricular biopsies collected before and after 0.3, 2, 5, 10 and 20 min of VF and global ischemia. Electrical activity was monitored via plunge needle electrodes and pseudo-ECG. Four out of nine hearts exhibited electrical failure at 10.1±0.9 min (early-asys), while 5/9 hearts maintained VF for at least 19.7 min (late-asys). As compared to late-asys, early-asys hearts had more ADP, less phosphocreatine, and higher levels of lactate at some time points during VF/ischemia (all comparisons p<0.05). Pre-ischemic samples from late-asys hearts contained ∼25 times more inorganic pyrophosphate (PPi) than early-asys hearts. A mechanistic role of PPi in cardioprotection was then tested by monitoring mitochondrial membrane potential (ΔΨ) during 20 min of simulated-demand ischemia using potentiometric probe TMRM in rabbit adult ventricular myocytes incubated with PPi versus control group. Untreated myocytes experienced significant loss of ΔΨ while in the PPi-treated myocytes ΔΨ was relatively maintained throughout 20 min of simulated-demand ischemia as compared to control (p<0.05)., Conclusions: High tissue level of PPi may prevent ΔΨm loss and electrical failure at the early phase of ischemic stress. The link between the two protective effects may involve decreased rates of mitochondrial ATP hydrolysis and lactate accumulation.

The heterogeneity of schizophrenia remains an obstacle for understanding its pathophysiology. Studies using a tone discrimination screening test to classify patients have found evidence for 2 subgroups having either a specific deficit in verbal working memory (WM) or deficits in both verbal and nonverbal memory. This study aimed to (a) replicate in larger samples differences between these subgroups in auditory verbal WM; (b) evaluate their performance on tests of explicit memory and sustained attention; (c) determine the relation of verbal WM deficits to auditory hallucinations and other symptoms; and (d) examine medication effects. The verbal WM and tone discrimination performance did not differ between medicated (n = 45) and unmedicated (n = 38) patients. Patients with schizophrenia who passed the tone screening test (discriminators; n = 60) were compared with those who did not (nondiscriminators; n = 23) and healthy controls (n = 47). The discriminator subgroup showed poorer verbal WM than did controls and a deficit in verbal but not visual memory on the Wechsler Memory Scale-Revised (Wechsler, 1987), whereas the nondiscriminator subgroup showed overall poorer performance on both verbal and nonverbal tests and a marked deficit in sustained attention. Verbal WM deficits in discriminators were correlated with auditory hallucinations but not with negative symptoms. The results are consistent with a verbal memory deficit in a subgroup of schizophrenia having intact auditory perception, which may stem from dysfunction of language-related cortical regions, and a more generalized cognitive deficit in a subgroup having auditory perceptual and attentional dysfunction., ((c) 2010 APA, all rights reserved.)

Examining visual word recognition memory (WRM) with nose-referenced EEGs, we reported a preserved ERP 'old-new effect' (enhanced parietal positivity 300-800 ms to correctly-recognized repeated items) in schizophrenia ([Kayser, J., Bruder, G.E., Friedman, D., Tenke, C.E., Amador, X.F., Clark, S.C., Malaspina, D., Gorman, J.M., 1999. Brain event-related potentials (ERPs) in schizophrenia during a word recognition memory task. Int. J. Psychophysiol. 34(3), 249-265.]). However, patients showed reduced early negative potentials (N1, N2) and poorer WRM. Because group differences in neuronal generator patterns (i.e., sink-source orientation) may be masked by choice of EEG recording reference, the current study combined surface Laplacians and principal components analysis (PCA) to clarify ERP component topography and polarity and to disentangle stimulus- and response-related contributions. To investigate the impact of stimulus modality, 31-channel ERPs were recorded from 20 schizophrenic patients (15 male) and 20 age-, gender-, and handedness-matched healthy adults during parallel visual and auditory continuous WRM tasks. Stimulus- and response-locked reference-free current source densities (spherical splines) were submitted to unrestricted Varimax-PCA to identify and measure neuronal generator patterns underlying ERPs. Poorer (78.2+/-18.7% vs. 87.8+/-11.3% correct) and slower (958+/-226 vs. 773+/-206 ms) performance in patients was accompanied by reduced stimulus-related left-parietal P3 sources (150 ms pre-response) and vertex N2 sinks (both overall and old/new effects) but modality-specific N1 sinks were not significantly reduced. A distinct mid-frontal sink 50-ms post-response was markedly attenuated in patients. Reductions were more robust for auditory stimuli. However, patients showed increased lateral-frontotemporal sinks (T7 maximum) concurrent with auditory P3 sources. Electrophysiologic correlates of WRM deficits in schizophrenia suggest functional impairments of posterior cortex (stimulus representation) and anterior cingulate (stimulus categorization, response monitoring), primarily affecting memory for spoken words.

The purpose of this study was to determine whether schizophrenia was associated with alterations in alcohol response that might explain the elevated risk for AUDs in this population. In a randomized, double-blind, placebo-controlled, counter-balanced 3 test day laboratory study, the effects of alcohol were compared in 23 subjects with schizophrenia (without any previous alcohol use disorder (AUD) but with some alcohol exposure) and in 14 healthy subjects matched for age, gender, education, and lifetime exposure to alcohol. Standard alcohol drinks in a scheduled design were administered to produce blood alcohol levels of 0, 0.02-0.04 mg%, or 0.06-0.08 mg%. Schizophrenia symptoms, perceptual alterations, stimulant and depressant subjective effects of alcohol, and 'high' were measured before alcohol administration and at several post-drug time points. Verbal learning and recall, vigilance and distractibility, and motor function were assessed once per test day. Relative to healthy subjects, subjects with schizophrenia reported greater euphoria and stimulatory effects in response to alcohol. Alcohol produced small transient increases in positive psychotic symptoms and perceptual alterations without affecting negative symptoms. Alcohol also impaired several aspects of immediate and delayed recall, and vigilance, and distractibility. Schizophrenia patients showed increased euphoric and stimulatory responses to alcohol. These exaggerated positive responses to alcohol doses may contribute to the increased risk for AUDs associated with schizophrenia. The absence of 'beneficial' effects of alcohol does not support a self-medication hypothesis of alcohol use in schizophrenia.

To disentangle subprocesses of verbal working memory deficits in schizophrenia, long EEG epochs (>10 s) were recorded from 13 patients and 17 healthy adults during a visual word serial position test. ERP generator patterns were summarized by temporal PCA from reference-free current source density (CSD) waveforms to sharpen 31-channel topographies. Patients showed poorer performance and reduced left inferior parietotemporal P3 source. Build-up of mid-frontal negative slow wave (SW) in controls during item encoding, integration, and active maintenance was absent in patients, whereas a sustained mid-frontal SW sink during the retention interval was comparable across groups. Mid-frontal SW sinks (encoding and retention periods) and posterior SW sinks and sources (encoding only) were related to performance in controls only. Data suggest disturbed processes in a frontal-parietotemporal network in schizophrenia, affecting encoding and early item storage.

Background: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/2C) receptors, were studied in 23 healthy male subjects., Methods: Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after., Results: Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol., Conclusions: Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.

A prior study found a selective deficit in verbal working memory in a subgroup of patients with schizophrenia who performed as well as healthy controls on a screening test of attention and auditory perception [Arch. Gen. Psychiatry 55 (1998) 1093]. Given the importance of defining pathophysiologically distinct subtypes of schizophrenia, the present study aimed to replicate and extend this finding. Patients with schizophrenia who passed the screening test (discriminators or Dsz patients) were compared to those who did not (nondiscriminators, NDsz patients), and healthy controls on a word serial position test (WSPT) and on other tests of verbal and nonverbal cognitive function. Dsz patients performed more poorly than controls on the WSPT and showed serial position effects consistent with a verbal memory deficit. They also showed a deficit in verbal memory but not visual memory on the Wechsler Memory Scale-Revised. In contrast, the NDsz patients showed overall poor performance on both verbal and nonverbal tests, consistent with a generalized deficit. Verbal working memory deficits were not related to education, gender, severity of symptoms, medication status, or hemispheric dominance for perceiving dichotic words. The findings add to growing evidence for the existence of a subgroup of schizophrenia having a specific verbal memory deficit that is not limited to working memory, but extends to learning and recall of verbal material.