Hypogammaglobulinemia: A contributing factor to multiple sclerosis fatigue?

OBJECTIVE: Fatigue is one of the most disabling and difficult to treat symptoms of autoimmune diseases and frequently presents in people with multiple sclerosis (PwMS). Hypogammaglobulinemia for immunoglobulin G (IgG) affects approximately 8-25% of PwMS. We performed a retrospective analysis to investigate the association of MS-fatigue and IgG hypogammaglobulinemia. METHODS: PwMS, treated at Eginition University Hospital Athens or at the University Hospital Bern, were included (n = 134 patients (Bern n = 99; Athens n = 35)). Mann Whitney U-test (MWT), ANOVA test, Chi2 test and multivariable linear regression models were run. RESULTS: 97/134 (72.4%) PwMS reported fatigue. In the multivariable linear regression analysis, IgG serum concentration (-1.6, 95%CI -2.7 - -0.5, p = 0.006), daytime sleepiness (0.8, 95%CI 0.2-1.4, p = 0.009), and a depressive mood (1.1, 95%CI 0.8-1.4, p < 0.001) were significantly associated with fatigue. The impact of IgG serum concentration (-2.9 95%CI -4.7 - -1.1, p = 0.002) remained significant also in the subcohort of PwMS without depressive symptoms or daytime sleepiness. CONCLUSIONS: We found an association between IgG hypogammaglobulinemia and fatigue in PwMS (Level of Evidence IV), which might be translated to other autoimmune diseases. It bears a potential therapeutic consequence considering IgG supplementation strategies, if our finding can be validated prospectively.

Electronic decay of core-excited HCl molecules probed by THz streaking.

The ultrafast electronic decay of HCl molecules in the time domain after resonant core excitation was measured. Here, a Cl-2p core electron was promoted to the antibonding σ* orbital initiating molecular dissociation, and simultaneously, the electronic excitation relaxes via an Auger decay. For HCl, both processes compete on similar ultrashort femtosecond time scales. In order to measure the lifetime of the core hole excitation, we collinearly superimposed 40 fs soft x-ray pulses with intense terahertz (THz) radiation from the free-electron laser in Hamburg (FLASH). Electrons emitted from the molecules are accelerated (streaked) by the THz electric field where the resulting momentum change depends on the field's phase at the instant of ionization. Evaluation of a time-shift between the delay-dependent streaking spectra of photo- and Auger electrons yields a decay constant of (11 ± 2) fs for LMM Auger electrons. For further validation, the method was also applied to the MNN Auger decay of krypton. Reproduction of the value already published in the literature confirms that a temporal resolution much below the duration of the exciting x-ray pulses can be reached.

The utility of an RDoC motor domain to understand psychomotor symptoms in depression.

Despite the clinical impact of motor symptoms such as agitation or retardation on the course of depression, these symptoms are poorly understood. Novel developments in the field of instrumentation and mobile devices allow for dimensional and continuous recording of motor behavior in various settings, particularly outside the laboratory. Likewise, the use of novel assessments enables to combine multimodal neuroimaging with behavioral measures in order to investigate the neural correlates of motor dysfunction in depression. The research domain criteria (RDoC) framework will soon include a motor domain that will provide a framework for studying motor dysfunction in mood disorders. In addition, new studies within this framework will allow investigators to study motor symptoms across different stages of depression as well as other psychiatric diagnoses. Finally, the introduction of the RDoC motor domain will help test how motor symptoms integrate with the original five RDoC domains (negative valence, positive valence, cognitive, social processes, and arousal/regulation).

Resting state perfusion in the language network is linked to formal thought disorder and poor functional outcome in schizophrenia.

OBJECTIVE: Formal thought disorder (FTD) is a core symptom in schizophrenia. Here, we focus on resting state cerebral blood flow (rCBF) linked to dimensions of FTD. METHODS: We included 47 schizophrenia spectrum patients and 30 age- and gender-matched healthy controls. We assessed FTD with the assessment of thought, language, and communication (TLC) and imaging on a 3T MRI scanner. Within patients, we tested the association of FTD dimensions and in a subgroup (n = 27) the association of functional outcome after 6 months with whole brain rCBF. RESULTS: Negative FTD was most prominently associated with perfusion within the superior temporal gyrus, while positive FTD was associated with perfusion within the supplementary motor area, and inferior frontal gyrus. Perfusion within the left supramarginal gyrus was associated with social functioning after 6 months. CONCLUSIONS: Distinguishable associations of rCBF with FTD dimensions point to distinct underlying pathophysiology. The location of aberrant perfusion patterns suggests that negative FTD might reflect defective access to semantic memory while positive FTD likely reflects defective suppression of irrelevant information during increased speech production. Finally, the neural correlates of thought block were also predictive of poor functional outcome. Thus, functional outcome and distinct FTD dimensions may share some pathophysiology.

Severe sepsis in the ICU is often missing in hospital discharge codes.

BACKGROUND: Different International Classification of Diseases (ICD)-based code abstraction strategies have been used when studying the epidemiology of severe sepsis. The aim of this study was to compare three previously used ICD code abstraction strategies to the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) consensus criteria for severe sepsis, in a setting of intensive care patients. METHODS: All patients (≥ 18 years of age) with severe sepsis according to the ACCP/SCCM criteria registered in the Swedish Intensive Care Registry (2005-2009) were included in the study. Using the Swedish National Patient Register, we investigated whether these patients fulfilled an ICD code compilation for severe sepsis at hospital discharge. RESULTS: Overall, 9271 patients with severe sepsis were registered in the Swedish Intensive Care Registry. A majority of these patients (55.4%) were discharged from the hospital with ICD codes that did not correspond to any of the ICD code compilations. A minority of patients (10.3%) were discharged with ICD codes corresponding to all three code abstraction strategies applied. Overall, the proportion of patients discharged with ICD codes corresponding to the criteria of Angus et al. was 15.1%, to the criteria of Flaatten was 39.8%, and to the criteria of Martin et al. was 16.0%. CONCLUSIONS: A majority of patients with severe sepsis according to the ACCP/SCCM criteria were not discharged with ICD codes corresponding to the ICD code abstraction strategies; thus, the abstraction strategies did not identify the correct patients.

Identifying opportunities to increase organ donation after brain death. An observational study in Sweden 2009-2014.

BACKGROUND: There is a wide gap between the number of organ donors and patients on waiting lists for transplantation. The purpose of this Swedish nationwide study of the critical pathway for organ donation after brain death (DBD) was to identify missed opportunities for organ donation. METHODS: We performed a prospective, observational study of all ICU deaths in Sweden from Jan 1, 2009 to Dec 31, 2014. The protocol structure followed the critical pathway for organ donation, which was developed and tested during 2008. We analysed differences in donation incidences between healthcare providers (counties) and patient characteristics using descriptive statistics and logistic regression. RESULTS: The number of DBD per million population (pmp) was 14.9, varying almost 10-fold from 4.3 to 40.6 DBD pmp between counties. Regional variation in DBD decreased when we assigned the donor to the place of residence (from 6.9 to 27.7 DBD pmp). Women were more likely to become donors compared to men [crude odds ratio (OR) 1.60, 95% confidence interval (CI) 1.38-1.85, P < 0.001]. The increased likelihood remained after adjusting for age, comorbidity, and main diagnostic categories (OR 1.49, 95% CI 1.25-1.77, P < 0.001). An end-of-life decision was found in 50.9% of possible organ donors. CONCLUSIONS: Regional differences in DBD were considerable, and women were more likely to become donors than men. There is a need for increased awareness of the potential for organ donation as an integral part of end-of-life clinical care. In-depth analysis of these differences may reveal opportunities for action that could lead to increased DBD.

Distinct resting-state perfusion patterns underlie psychomotor retardation in unipolar vs. bipolar depression.

OBJECTIVE: Psychomotor abnormalities characterize both unipolar (UP) depression and bipolar (BP) depression. We aimed to assess their neurobiological correlates in terms of motor activity (AL) and resting-state cerebral blood flow (rCBF) and investigate their association in BP, UP, and healthy controls (HC). METHOD: We enrolled 42 depressed patients (22 BP, 20 UP) and 19 HC matched for age, gender, education, income. AL and rCBF were objectively assessed with the use of wrist actigraphy and arterial spin labeling. Group differences and the association of AL and rCBF were computed. RESULTS: Activity level was significantly reduced in patients, but no difference was found between BP and UP. Increased perfusion was found in BP compared with UP and HC, in multiple brain areas. We found positive correlations of rCBF and AL in BP and UP, in different parts of the insula and frontal regions. Only BP showed a cluster in the left precentral gyrus. In HC, only inverse correlations of AL and rCBF were found. CONCLUSION: The differences in rCBF and in the localization of the clusters of positive AL/rCBF correlations between BP and UP suggest that different neural impairments may underlie motor symptoms in the two disorders, but finally converge in phenotypically similar manifestations.

Keep at bay!--Abnormal personal space regulation as marker of paranoia in schizophrenia.

BACKGROUND: During threat, interpersonal distance is deliberately increased. Personal space regulation is related to amygdala function and altered in schizophrenia, but it remains unknown whether it is particularly associated with paranoid threat. METHODS: We compared performance in two tests on personal space between 64 patients with schizophrenia spectrum disorders and 24 matched controls. Patients were stratified in those with paranoid threat, neutral affect or paranoid experience of power. In the stop-distance paradigm, participants indicated the minimum tolerable interpersonal distance. In the fixed-distance paradigm, they indicated the level of comfort at fixed interpersonal distances. RESULTS: Paranoid threat increased interpersonal distance two-fold in the stop-distance paradigm, and reduced comfort ratings in the fixed-distance paradigm. In contrast, patients experiencing paranoid power had high comfort ratings at any distance. Patients with neutral affect did not differ from controls in the stop-distance paradigm. Differences between groups remained when controlling for gender and positive symptom severity. Among schizophrenia patients, the stop-distance paradigm detected paranoid threat with 93% sensitivity and 83% specificity. CONCLUSIONS: Personal space regulation is not generally altered in schizophrenia. However, state paranoid experience has distinct contributions to personal space regulation. Subjects experiencing current paranoid threat share increased safety-seeking behavior.

EEG marker of inhibitory brain activity correlates with resting-state cerebral blood flow in the reward system in major depression.

Frontal alpha band asymmetry (FAA) is a marker of altered reward processing in major depressive disorder (MDD), associated with reduced approach behavior and withdrawal. However, its association with brain metabolism remains unclear. The aim of this study was to investigate FAA and its correlation with resting-state cerebral blood flow (rCBF). We hypothesized an association of FAA with regional rCBF in brain regions relevant to reward processing and motivated behavior, such as the striatum. We enrolled 20 patients and 19 healthy subjects. FAA scores and rCBF were quantified with the use of EEG and arterial spin labeling. Correlations of the two were evaluated, as well as the association with FAA and psychometric assessments of motivated behavior and anhedonia. Patients showed a left-lateralized pattern of frontal alpha activity and a correlation of FAA lateralization with subscores of Hamilton Depression Rating Scale linked to motivated behavior. An association of rCBF and FAA scores was found in clusters in the dorsolateral prefrontal cortex bilaterally (patients), in the left medial frontal gyrus, in the right caudate head and in the right inferior parietal lobule (whole group). No correlations were found in healthy controls. Higher inhibitory right-lateralized alpha power was associated with lower rCBF values in prefrontal and striatal regions, predominantly in the right hemisphere, which are involved in the processing of motivated behavior and reward. Inhibitory brain activity in the reward system may contribute to some of the motivational problems observed in MDD.

[Schizophrenic Psychoses with Motor-Dominant Symptoms: Considerations for a System-Specific Approach]. / Schizophrene Psychosen mit motordominanter Symptomatik: Überlegungen zu einem systemspezifischen Ansatz.

In order to reduce heterogeneity in schizophrenia, a system-specific approach consisting of the domains "language", "affect" and "motor behavior" has been proposed. We examined this system-specific approach for its applicability to clinical practice in the motor behavior domain, using the methodological approach of case studies, and discuss here the differences to the positive/negative concept. We analyzed eight cases with stable motor-dominant symptoms, and also quantitatively assessed motor behavior by using the Bern Psychopathology Scale (BPS), a standardized psychopathological assessment instrument, as well as actigraphic data. Characterization of cases using the positive/negative approach was not helpful. We found an overlap of the motor behavior domain with the other two domains. This complicates the application of the system-specific approach in the sense of a typology. Furthermore, we found both relapsing courses with full remission and chronic courses with deterioration within the motor-dominant subtype. Nevertheless, the system-specific approach has heuristic utility for the future.

Subtyping schizophrenia: A comparison of positive/negative and system-specific approaches.

BACKGROUND: Schizophrenia is a heterogeneous disorder. Over the years, different approaches have been proposed to approach this heterogeneity by categorizing symptom patterns. The study aimed to compare positive/negative and system-specific approaches to subtyping. METHODS: We used the Positive and Negative Syndrome Scale (PANSS) and Bern Psychopathology Scale (BPS), which consists of subscales for three domains (language, affect and motor behavior) that are hypothesized to be related to specific brain circuits, to assess cross-sectional psychopathological characteristics in a sample of 100 inpatients with schizophrenia spectrum disorders. We then categorized participants into positive/negative and system-specific subgroups to allow comparisons of the two approaches. RESULTS: The analyses revealed correlations between the PANSS positive subscore and the BPS affective subscore (r=.446, p<.001) and between the PANSS negative subscore and the BPS motor behavior subscore (r=.227, p=.023). As regards the positive and negative subtype, more participants were classified as positive in the language-dominant subtype (30.3%) and affect-dominant subtype (30.3%), whereas more were classified as negative in the motor behavior-dominant subtype (44.4%). However, most patients met the criteria for the mixed subtype. CONCLUSIONS: The results suggest that the positive/negative and system-specific approaches can be regarded as complementary. Future studies should examine both approaches in a longitudinal assessment of psychopathological symptoms and link them with qualitative-phenomenological approaches.

In-hospital vs. 30-day mortality in the critically ill - a 2-year Swedish intensive care cohort analysis.

BACKGROUND: Standardised mortality ratio (SMR) is a common quality indicator in critical care and is the ratio between observed mortality and expected mortality. Typically, in-hospital mortality is used to derive SMR, but the use of a time-fixed, more objective, end-point has been advocated. This study aimed to determine the relationship between in-hospital mortality and 30-day mortality on a comprehensive Swedish intensive care cohort. METHODS: A retrospective study on patients >15 years old, from the Swedish Intensive Care Register (SIR), where intensive care unit (ICU) admissions in 2009-2010 were matched with the corresponding hospital admissions in the Swedish Hospital Discharge Register. Recalibrated SAPS (Simplified Acute Physiology Score) 3 models were developed to predict and compare in-hospital and 30-day mortality. SMR based on in-hospital mortality and on 30-day mortality were compared between ICUs and between groups with different case-mixes, discharge destinations and length of hospital stays. RESULTS: Sixty-five ICUs with 48861 patients, of which 35610 were SAPS 3 scored, were included. Thirty-day mortality (17%) was higher than in-hospital mortality (14%). The SMR based on 30-day mortality and that based on in-hospital mortality differed significantly in 7/53 ICUs, for patients with sepsis, for elective surgery-admissions and in groups categorised according to discharge destination and hospital length of stay. CONCLUSION: Choice of mortality end-point influences SMR. The extent of the influence depends on hospital-, ICU- and patient cohort characteristics as well as inter-hospital transfer rates, as all these factors influence the difference between SMR based on 30-day mortality and SMR based on in-hospital mortality.

Prenatal diagnosis in haemophilia A: experience of the genetic diagnostic laboratory.

The paper describes the experience of the Genetic Diagnostic Laboratory in prenatal testing for haemophilia A, an X-linked recessive disease caused by mutations in the F8 gene. Knowledge of a familial mutation prior to pregnancy can benefit prenatal diagnosis and decrease wait time for molecular testing during pregnancy. This is a retrospective review of a series of pregnant women who pursued F8 gene testing from December 1997 through May 2012, highlighting three cases, which demonstrate the technical complexities of analysis and the implications of not knowing carrier status prior to pregnancy. Mutations of the F8 gene were detected in affected males, obligate female carriers and suspected female carriers by DNA sequencing, inverse-PCR, qRT-PCR, Southern blot and exonic dosage analysis. The same methods were used to analyse prenatal samples from obligate or suspected female carriers upon request. Maternal cell contamination studies were performed for all prenatal samples analysed. Ninety-nine women pursued F8 testing during pregnancy, either for carrier status alone or carrier status and prenatal diagnosis. Ninety-one women (91%) requested carrier testing because they did not know their F8 mutation carrier status prior to pregnancy. Eight women requested prenatal diagnosis only, and only 4 of these were aware of their mutation status. Thirty-seven individuals were found to be mutation carriers. Forty-two prenatal samples were received for prenatal diagnosis. In total 21 foetuses were identified as mutation carriers. Mutation detection was complex and increased the turnaround time in some cases. Only four of 99 women who submitted samples for F8 testing were aware of their F8 mutation status prior to pregnancy. Knowledge of F8 mutation status prior to pregnancy allows for efficient prenatal diagnosis, when desired. Thus, preconception genetic counselling is required to inform patients of the available options and the complex and time-consuming nature of F8 testing.

EuroSCORE II and N-terminal pro-B-type natriuretic peptide for risk evaluation: an observational longitudinal study in patients undergoing coronary artery bypass graft surgery.

BACKGROUND: Postoperative heart failure remains the major cause of death after cardiac surgery. As N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a predictor for postoperative heart failure, the aim was to evaluate if preoperative NT-proBNP could provide additional prognostic information to the recently launched EuroSCORE II. METHODS: A total of 365 patients with acute coronary syndrome (ACS) undergoing isolated coronary artery bypass graft (CABG) surgery were studied prospectively. Preoperative NT-proBNP and EuroSCORE II were evaluated with regard to severe circulatory failure after operation according to prespecified criteria. To assess what clinical outcomes are indicated by NT-proBNP levels in different risk categories, the patients were stratified according to EuroSCORE II. Based on receiver operating characteristics analysis, these cohorts were assessed with regard to preoperative NT-proBNP below or above 1028 ng litre(-1). The follow-up time averaged 4.4 (0.7) yr. RESULTS: Preoperative NT-proBNP≥1028 ng litre(-1) [odds ratio (OR) 9.9, 95% confidence interval (CI) 1.01-98.9; P=0.049] and EuroSCORE II (OR 1.24, 95% CI 1.06-1.46; P=0.008) independently predicted severe circulatory failure after operation. In intermediate-risk patients (EuroSCORE II 2.0-10.0), NT-proBNP≥1028 ng litre(-1) was associated with a higher incidence of severe circulatory failure (6.6% vs 0%; P=0.007), renal failure (14.8% vs 5.4%; P=0.03), stroke (6.6% vs 0.7%; P=0.03), longer intensive care unit stay [37 (35) vs 27 (38) h; P=0.002], and worse long-term survival. CONCLUSIONS: Combining EuroSCORE II and preoperative NT-proBNP appears to improve risk prediction with regard to severe circulatory failure after isolated CABG for ACS. NT-proBNP may be particularly useful in patients at intermediate risk according to EuroSCORE II. CLINICAL TRIAL REGISTRATION: NCT00489827.

A generic simulation model for planning critical care resource requirements.

Intensive care capacity planning based on factual or forecasted mean admission numbers and mean length of stay without taking non-linearity and variability into account is fraught with error. Simulation modelling may allow for a more accurate assessment of capacity needs. We developed a generic intensive care simulation model using data generated from anonymised patient records of all admissions to four different hospital intensive care units. The model was modified and calibrated stepwise to identify important parameters and their values to obtain a match between model predictions and actual data. The most important characteristic of the final model was the dependency of admission rate on actual occupancy. Occupancy, coverage and transfers of the final model were found to be within 2% of the actual data for all four simulated intensive care units. We have shown that this model could provide accurate decision support for planning critical care resource requirements.

What determines immediate use of invasive ventilation in patients with COPD?

BACKGROUND: The choice between non-invasive ventilation (NIV) and invasive ventilation in patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may be irrational. The aim of this study was to examine those patient characteristics, and circumstances deemed important in the choice made between NIV and invasive ventilation in the intensive care unit (ICU). METHODS: We first examined 95 admissions of AECOPD patients on nine ICUs and identified variables associated with invasive ventilation. Thereafter, a questionnaire was sent to ICU personnel to study the relative importance of different factors with a possible influence on the decision to use invasive ventilation at once. RESULTS: Univariable analysis showed that increasing age [odds ratio (OR) 1.06 per year] and increasing body mass index (BMI) (OR 1.11 per kg/m(2) ) were associated with immediate invasive ventilation, while there was no such association with arterial blood gases or breath rate. BMI was the only factor that remained associated with immediate invasive ventilation in the multivariable analysis [OR 1.12 (95% confidence interval 1.03-1.23) kg/m(2) ]. Ranking of responses to the questionnaire showed that consciousness, respiratory symptoms and blood gases were powerful factors determining invasive ventilation, whereas high BMI and age were ranked low. Non-patient-related factors were also deemed important (physician in charge, presence of guidelines, ICU workload). CONCLUSION: Factors other than those deemed most important in guidelines appear to have an inappropriate influence on the choice between NIV and immediate intubation in AECOPD in the ICU. These factors must be identified to further increase the appropriate use of NIV.

Inhibition of adrenergic human prostate smooth muscle contraction by the inhibitors of c-Jun N-terminal kinase, SP600125 and BI-78D3.

BACKGROUND AND PURPOSE α(1) -Adrenoceptor-induced contraction of prostate smooth muscle is mediated by calcium- and Rho kinase-dependent mechanisms. In addition, other mechanisms, such as activation of c-jun N-terminal kinase (JNK) may be involved. Here, we investigated whether JNK participates in α(1)-adrenoceptor-induced contraction of human prostate smooth muscle. EXPERIMENTAL APPROACH Prostate tissue was obtained from patients undergoing radical prostatectomy. Effects of the JNK inhibitors SP600125 (50 µM) and BI-78D3 (30 µM) on contractions induced by phenylephrine, noradrenaline and electric field stimulation (EFS) were studied in myographic measurements. JNK activation by noradrenaline (30 µM) and phenylephrine (10 µM), and the effects of JNK inhibitors of c-Jun phosphorylation were assessed by Western blot analyses with phospho-specific antibodies. Expression of JNK was studied by immunohistochemistry and fluorescence double staining. KEY RESULTS The JNK inhibitors SP600125 and BI-78D3 reduced phenylephrine- and noradrenaline-induced contractions of human prostate strips. In addition, SP600125 reduced EFS-induced contraction of prostate strips. Stimulation of prostate tissue with noradrenaline or phenylephrine in vitro resulted in activation of JNK. Incubation of prostate tissue with SP600125 or BI-78D3 reduced the phosphorylation state of c-Jun. Immunohistochemical staining demonstrated the expression of JNK in smooth muscle cells of human prostate tissue. Fluorescence staining showed that α(1A)-adrenoceptors and JNK are expressed in the same cells. CONCLUSIONS AND IMPLICATIONS Activation of JNK is involved in α(1)-adrenoceptor-induced prostate smooth muscle contraction. Models of α(1)-adrenoceptor-mediated prostate smooth muscle contraction should include this JNK-dependent mechanism.

Neural correlates of disbalanced motor control in major depression.

BACKGROUND: Motor retardation is a common symptom of major depressive disorder (MDD). Despite the existence of various assessment methods, little is known on the pathobiology of motor retardation. We aimed to elucidate aspects of motor control investigating the association of objective motor activity and resting state cerebral blood flow (CBF). METHODS: Nineteen control subjects and 20 MDD patients were investigated using arterial spin labeling (ASL) at 3T in the morning to quantify resting state CBF. Afterwards wrist actigraphy was recorded for 24h. CBF, group and activity level (AL) were entered into a whole brain general linear model. RESULTS: MDD patients had reduced AL. Both groups had linear associations of AL and CBF in bilateral rostral prefrontal cortex. Groups differed in four clusters associated with motor control. In controls a positive association was found in the left caudal cingulate zone (CCZ) and an inverse association in the right external globus pallidus (GPe). MDD patients had positive associations in the right orbitofrontal cortex and inverse associations in the left supplemental motor area. LIMITATIONS: Patients were on antidepressant medication. CONCLUSIONS: The pattern of associations between CBF and AL suggest disbalanced motor control in MDD. Findings are in line with the hypothesis of dopamine deficits contributing to motor retardation in MDD.