Epidural analgesia and perioperative kidney function after major liver resection.

BACKGROUND: Epidural analgesia (EDA) is a common analgesia regimen in liver resection, and is accompanied by sympathicolysis, peripheral vasodilatation and hypotension in the context of deliberate intraoperative low central venous pressure. This associated fall in mean arterial pressure may compromise renal blood pressure autoregulation and lead to acute kidney injury (AKI). This study investigated whether EDA is a risk factor for postoperative AKI after liver surgery. METHODS: The incidence of AKI was investigated retrospectively in patients who underwent liver resection with or without EDA between 2002 and 2012. Univariable and multivariable analyses were performed including recognized preoperative and intraoperative predictors of posthepatectomy renal failure. RESULTS: A series of 1153 patients was investigated. AKI occurred in 8·2 per cent of patients and was associated with increased morbidity (71 versus 47·3 per cent; P = 0·003) and mortality (21 versus 0·3 per cent; P < 0·001) rates. The incidence of AKI was significantly higher in the EDA group (10·1 versus 3·7 per cent; P = 0·003). Although there was no significant difference in the incidence of AKI between patients undergoing minor hepatectomy with or without EDA (5·2 versus 2·7 per cent; P = 0·421), a substantial difference in AKI rates occurred in patients undergoing major hepatectomy (13·8 versus 5·0 per cent; P = 0·025). In multivariable analysis, EDA remained an independent risk factor for AKI after hepatectomy (P = 0·040). CONCLUSION: EDA may be a risk factor for postoperative AKI after major hepatectomy.

Aberrant regulation of the integrin very late antigen-4 in systemic lupus erythematosus.

Integrin very late antigen-4 (VLA4) is induced during inflammation and can regulate monocyte migration. It has been implicated in atherogenesis, a significant concern in systemic lupus erythematosus (SLE). The aim of this study was to define VLA4 expression in SLE monocytes. Flow cytometry, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry staining with confocal microscopy were used to evaluate VLA4 expression in SLE patients and controls. We found elevated expression of VLA4 in SLE patients with significantly increased VLA4 staining intracellularly compared to control. Exposure of control monocytes to SLE sera or immune complexes led to increased intracellular expression, and immune complexes were capable of driving redistribution of surface VLA4 to the cytoplasm. Therefore, VLA4 was found to be subject to complex regulation with SLE sera driving both RNA expression and redistribution of protein. Stimulation of SLE monocytes with a VLA4 ligand induced significant TNFα expression, confirming a functional effect. This behavior may contribute to increased atherosclerosis and monocyte infiltrates in end organs.

ABC Schizophrenia study: an overview of results since 1996.

PURPOSE: The ABC Schizophrenia study, led by a single research team, investigated a schizophrenia sample systematically over quarter of a century. This paper summarises results from 1996 onwards. The initial goals were to explain the considerably higher age at first admission in women, and to obtain precise information on the onset and early course of schizophrenia as a prerequisite for early intervention. METHOD: The study was hypothesis-driven. People with schizophrenia were compared in the prodrome and at first admission to those with unipolar depression and to healthy controls. We analysed the medium-term (5-year) and the long-term (12-year) course of schizophrenia, its symptom dimensions, social parameters and predictors. SAMPLES: (1) 276 population-based first admissions (232 first episodes) of schizophrenia (age range 12-59 years); (2) a subsample of 130 first admissions for schizophrenia; (3) 130 first admissions for unipolar depression; (4) 130 healthy population controls and (5) 1,109 consecutive first admissions for schizophrenia spectrum disorder without an age limit. RESULTS: The prodromal stages of schizophrenia and depression were very similar until positive symptoms appeared. The most frequent symptom in schizophrenia was depressed mood. The course of psychosis from prodrome to 12 years following first admission was very variable. From 5 to 12 years after first admission the course was characterised by irregular exacerbations of the main symptom dimensions, with no overall deterioration or improvement. CONCLUSIONS: Schizophrenic psychosis and severe affective disorder, rather than representing discrete illnesses, probably mark different stages in the manifestation of psychopathology produced by various degrees of brain dysfunction.

[Schizophrenia - a disorder in its own right?: results from 25 years of the ABC study]. / Schizophrenie - eine einheitliche Krankheit?: Ergebnisse aus 25 Jahren ABC-Studie.

BACKGROUND: The ABC schizophrenia study conducted by the same team over 25 years initially aimed at illuminating the onset, prodromal stage and sex differences in age at first hospitalization in schizophrenia. New hypotheses were systematically generated from the results achieved. METHODS: A population-based sample of 276 first admission cases (232 first episodes, age 12-59 years), including a subsample of 130 first admissions (115 first episodes), were assessed to study prodromal stage, first illness episode, medium and long-term course and symptom dimensions in schizophrenia. The samples were compared with age and sex-matched healthy controls and with patients first admitted for unipolar depression. A total of 1,109 consecutive first admissions for schizophrenia spectrum disorders independent from the other study samples were assessed to study changes in symptomatology across the age range. RESULTS: Before the onset of psychotic symptoms the prodromal stages of schizophrenia and severe and moderately severe depression are difficult to distinguish. The most frequent symptom in the course of schizophrenia, depressed mood, also represents the most frequent initial symptom in both disorders. Prodromal depression is a predictor of more depressive and positive symptoms in the first episode but not in the further course of the illness. Psychosis incidence for men, diagnosed according to ICD 9 (295, 297, 298.3/4), shows a pronounced peak at age 15-24 years, for women a lower peak at age 15-29 years and a second, still lower peak at the menopausal age of 45-49 years. The explanation, confirmed in animal experiments, lies in a protective effect of estrogen due to reduced D2 receptor sensitivity. The effect is antagonized by an elevated genetic risk. Functional and social impairment emerge even at the prodromal stage and the severity depends on sex and social status. Young men with schizophrenia show a less favorable social course because of the earlier age of onset and socially adverse illness behavior. Late onset is associated with a milder, primarily paranoid symptomatology and less severe social impairment. Schizophrenia is a disorder of all ages showing roughly equal life time incidence rates for men and women but considerable difference in certain periods of age. The symptom dimensions show a plateau-like course 2-5 years after the first episode. Hidden behind this picture are irregular symptom exacerbations which vary in duration. Schizophrenia conveys the picture of recurrent vulnerability to crisis and not of a stable residual state of disordered brain development or of a progressive neurodegenerative process.

Preventing progression to first-episode psychosis in early initial prodromal states.

BACKGROUND: Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred. AIMS: To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive-behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS. METHOD: A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: NCT00204087). Primary outcome was progression to psychosis at 12- and 24-month follow-up. RESULTS: A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008) and at 24-month follow-up (6.3% v. 20.0%; P = 0.019). CONCLUSIONS: Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS.

Spinal subdural effusion - an additional sonographic sign of child abuse.

PURPOSE: To assess the suitability of spinal ultrasound for the detection of spinal subdural hematoma in infants with sustained non-accidental trauma. MATERIALS AND METHODS: Six infants (mean age ± SD 3.3 ± 1.5 months) admitted to our hospital because of suspected non-accidental trauma were examined radiologically with ultrasound, CT and/or MRI and skeletal radiography. Twelve healthy infants (mean age ± SD 2.5 ± 1.4 months) in whom an ultrasound of the spine was performed to exclude spinal dysraphism served as controls. RESULTS: All six patients with non-accidental trauma (NAT) presented with cranial subdural hematoma visualized by ultrasound and CT scan or MRI. Spinal ultrasound detected echogenic effusions with floating particles that displaced the undulating arachnoidea from the dura mater spinalis in all six patients with NAT. The size of the spinal subdural hematoma varied and extended from the cervical spine to the cauda equina. The anatomic landmarks (dura mater spinalis, arachnoidea spinalis) were identified and confirmed the subdural location. All spinal subdural hematomas were asymptomatic and detected by diagnostic ultrasound. None of the infants had a pre-existing neurological or hemorrhagic disorder. The plain X-rays of the spine in these infants showed no osseous lesion. Spinal subdural hematoma was not observed in any of the controls. CONCLUSION: The presence of spinal subdural hematoma is a valuable sign of sustained non-accidental trauma in infants that can be quickly and easily detected using spinal ultrasound without the need for sedation or general anesthesia. Thus, spinal ultrasound should be part of the imaging examinations performed in infants with suspected abuse.

Monocyte polarization: the relationship of genome-wide changes in H4 acetylation with polarization.

The character of monocytes is both molded by and contributes to ongoing immune responses. We hypothesized that monocyte polarization could have durable qualities and these would be mediated partly by changes in the chromatin. We defined genome-wide expression and histone H4 acetylation (H4ac) changes after γ-interferon (IFN), α-IFN and interleukin-4 treatment. To identify genes with altered potential for expression, we stimulated polarized monocytes and identified genes up- or downregulated after polarization and stimulation but not either treatment alone. We also defined durability after an 18-h or 3-day washout. Genes uniquely regulated after the combination of polarization and stimulus were durably altered, with 51% of the effects being durable. This gene set was highly enriched for cytokine-induced alterations in H4ac, with P-values ranging from 10(-24) to 10(-37). Certain regulons defined by patterns of expression were also associated with altered H4ac, with P-values ranging from 10(-4) to 10(-29). Networking software revealed a high density of mitogen-activated protein (MAP) kinase nodes in these clusters. Therefore, some changes in monocyte gene expression were sustained over a 3-day period. These durably altered gene sets were enriched for changes in H4ac and were associated with potential MAP kinase effects.

Global H4 acetylation analysis by ChIP-chip in systemic lupus erythematosus monocytes.

Systemic lupus erythematosus (SLE) is a polygenic disorder affecting approximately 1 in 1000 adults. Recent data have implicated interferons (IFN) in the pathogenesis, and the expressions of many genes downstream of IFNs are regulated at the level of histone modifications. We examined H4 acetylation (H4ac) and gene expression in monocytes from patients with SLE to define alterations to the epigenome. Monocytes from 14 controls and 24 SLE patients were used for analysis by chromatin immunoprecipitation for H4ac and gene expression arrays. Primary monocytes treated with alpha-IFN were used as a comparator. Data were analyzed for concordance of H4ac and gene expression. Network analyses and transcription factor analyses were conducted to identify potential pathways. H4ac was significantly altered in monocytes from patients with SLE. In all, 63% of genes with increased H4ac had the potential for regulation by IFN regulatory factor (IRF)1. IRF1 binding sites were also upstream of nearly all genes with both increased H4ac and gene expression. alpha-IFN was a significant contributor to both expression and H4ac patterns, but the greatest concordance was seen in the enrichment of certain transcription factor binding sites upstream of genes with increased H4ac in SLE and genes with increased H4ac after alpha-IFN treatment.

Changes in axonal excitability of primary sensory afferents with general anaesthesia in humans.

BACKGROUND: Intraoperative monitoring of neuronal function is important in a variety of surgeries. The type of general anaesthetic used can affect the interpretation and quality of such recordings. Although the principal effects of general anaesthetics are synaptically mediated, the extent to which they affect excitability of the peripheral afferent nervous system is unclear. METHODS: Forty subjects were randomized in a stratified manner into two groups, anaesthetized with either propofol or sevoflurane. The threshold tracking technique (QTRAC(®)) was used to measure nerve excitability parameters of the sensory action potential of the median nerve before and after induction of general anaesthesia. RESULTS: Several parameters of peripheral sensory afferent nerve excitability changed after induction of general anaesthesia, which were similar for both propofol and sevoflurane. The maximum amplitude of the sensory nerve action potential decreased in both groups (propofol: 25.3%; sevoflurane: 29.5%; both P<0.01). The relative refractory period [mean (sd)] also decreased similarly in both groups [propofol: -0.6 (0.7) ms; sevoflurane: -0.3 (0.5) ms; both P<0.01]. Skin temperature at the stimulation site increased significantly in both groups [propofol: +1.2 (1.0)°C; sevoflurane: +1.7 (1.4)°C; both P<0.01]. CONCLUSIONS: Small changes in excitability of primary sensory afferents after the induction of anaesthesia with propofol or sevoflurane were detected. These effects, which were non-specific and are possibly explained by changes observed in temperature, demonstrate possible anaesthetic effects on intraoperative neuromonitoring.

Heterologous expression and characterization of choline oxidase from the soil bacterium Arthrobacter nicotianae.

In the course of a microbial screening of soil samples for new oxidases, different enrichment strategies were carried out. With choline as the only carbon source, a microorganism was isolated and identified as Arthrobacter nicotianae. From this strain, a gene coding for a choline oxidase was isolated from chromosomal DNA. This gene named codA was cloned in Escherichia coli BL21-Gold and the protein (An_CodA) heterologously overexpressed as a soluble intracellular protein of 59.1 kDa. Basic biochemical characterization of purified protein revealed a pH optimum of 7.4 and activity over a broad temperature range (15-70 degrees C). Specific activities were determined toward choline chloride (4.70 +/- 0.12 U/mg) and the synthetic analogs bis(2-hydroxyethyl)-dimethylammonium chloride (0.05 +/- 0.45 x 10(-2) U/mg) and tris-(2-hydroxyethyl)-methylammonium methylsulfate (0.01 +/- 0.12 x 10(-2) U/mg). With increasing number of oxidizable groups, a significant decrease in activity was noted. Determination of kinetic parameters in atmorspheric oxygen resulted in K (M) = 1.51 +/- 0.09 mM and V (max) = 42.73 +/- 0.42 mU/min for choline chloride and K (M) = 4.77 +/- 0.76 mM and V (max) = 48.40 +/- 2.88 mU/min for the reaction intermediate betaine aldehyde respectively. Nuclear magnetic resonance spectroscopic analysis of the products formed during the enzyme reaction with choline chloride showed that in vitro the intermediate betaine aldehyde exists also free in solution.

Kidney Failure After Occlusion of Accessory Renal Arteries in Endovascular Abdominal Aneurysm Repair.

PURPOSE: To evaluate the incidence of acute renal failure and chronic kidney disease due to occlusion of accessory renal arteries during endovascular aneurysm repair of infrarenal abdominal aortic aneurysm. MATERIAL AND METHODS: We retrospectively reviewed the course of 181 patients (mean age, 71, SD ± 9  years) who underwent EVAR of infrarenal abdominal aortic aneurysm. The renal vessel anatomy was analyzed in all pre- and postoperative CT scans. Diameter and origin of accessory renal arteries were evaluated. Renal function was determined by pre- and postoperative serum creatinine and eGFR levels. Long-term follow-up (>3 months) of patients was available in 121 cases (66.9%). Acute kidney injury and chronic kidney failure were defined according to guidelines of "Kidney Disease: Improving Global Outcomes" (KDIGO). RESULTS: In 65 of 181 patients (33.9%), 82 accessory renal arteries were identified preoperatively. In 19 of 181 patients (10.5%), one or more accessory renal arteries were covered and subsequently occluded by the implanted stent-graft device. Neither acute kidney injury (10.3% vs 12.5%; p = .785) nor chronic kidney disease (10.7% vs 15.38%; p = .452) was detected significantly more often in patients with covered accessory renal artery. The only significant predictor of acute kidney injury was the preoperative serum creatinine level (1.12 mg/dl vs. 0.98 mg/dl; p = .03). Significant predictors for chronic kidney disease were preoperative serum creatinine, eGFR, and impaired renal function (p < .001). CONCLUSION: Coverage of accessory renal artery due to stent-graft does not lead either to temporary acute kidney injury after endovascular aneurysm repair or to chronic kidney disease. LEVEL OF EVIDENCE: Level II b.

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide.

OBJECTIVE: Based on the reported association between cytokines with depression and suicide, and evidence of increased markers of inflammation in the brain of suicide victims, the present study examined the expression of cytokines in the orbitofrontal cortex of suicide victims. METHOD: In a postmortem sample obtained from the Brodman area 11 of suicides (n = 34) and controls (n = 17), real-time RT-PCR was used to compare the expression of mRNA species for tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, 4, 5, 6, and 13. RESULTS: Increased expression of IL-4 was found in women suicide victims and IL-13 in men suicide victims. Elevated but not significant cytokine expression was also observed for TNF-alpha in women suicide victims. CONCLUSION: To our knowledge, these results provide the first evidence of the presence of mRNA transcripts of type 2 T-helper cytokines in the human orbitofrontal cortex and their increased expression in the brain of suicides.

Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction, increased oxidative stress and elevated apoptosis. Until now, AD cannot be diagnosed by a valid clinical method or a biomarker before the disease has progressed so far that dementia is present. Furthermore, no valid method is available to determine which patient with mild cognitive impairment (MCI) will progress to AD. Therefore, a correct diagnosis in the early stage of AD is not only of importance considering that early drug treatment is more effective but also that the psychological burden of the patients and relatives could be decreased. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as biomarker for AD in a peripheral cell model, the lymphocytes.

Acute effects of treatment for prodromal symptoms for people putatively in a late initial prodromal state of psychosis.

BACKGROUND: People in a putatively late prodromal state not only have an enhanced risk for psychosis but already suffer from mental and functional disturbances. AIMS: To evaluate the acute effects of a combined supportive and antipsychotic treatment on prodromal symptoms. METHOD: Putatively prodromal individuals were randomly assigned to a needs-focused intervention without (n=59) or with amisulpride (n=65). Outcome measures at 12-weeks effects were prodromal symptoms, global functioning and extrapyramidal side-effects. RESULTS: Amisulpride plus the needs-focused intervention produced superior effects on attenuated and full-blown psychotic symptoms, basic, depressive and negative symptoms, and global functioning. Main side-effects were prolactin associated. CONCLUSIONS: Coadministration of amisulpride yielded a marked symptomatic benefit. Effects require confirmation by a placebo-controlled study.

[Early diagnosis of schizophrenia]. / Checkliste fürr die Hausarztpraxis in Arbeit. Erste Signale einer Psychose richtig deuten.

Efforts to achieve early detection of and timely intervention in incipient psychotic conditions are characteristic of an extremely innovative area of schizophrenia research over the last ten years or more. Within the Competency Network on Schizophrenia, the Early Recognition Inventory, ERIraos was developed and tested with the aim of identifying persons at an elevated risk of developing a psychosis, and providing them with timely treatment. In this study, the early diagnostic work-up and intervention were performed at the early intervention centers located in Bonn, Düsseldorf, Cologne and Munich. The initial results regarding transition to a psychosis based on 1 year follow-up data are now available.The outcomes of these analyses form the basis for the revision of the Early Recognition Inventory, with the aim of bringing it into line with the requirements met with in practice.

Adaptation of the WHO guideline for residual DNA in parenteral vaccines produced on continuous cell lines to a limit for oral vaccines.

Although there is a WHO guidance for a limit on residual DNA for parenterally administered vaccines produced on continuous cell lines, there is no corresponding guidance for oral vaccines. To help determine an oral limit, we performed a study of Vero cell DNA uptake in rats, in which the relative uptake and persistence of Vero cell DNA administered orally was compared to its uptake when delivered intramuscularly (IM). The results of this study allowed the generation of an empirically derived IM versus oral factor (10(6)) representing the relative inefficiency of DNA uptake by oral administration. This factor was then applied to the WHO recommended parenteral limit of 10 ng/dose to determine a corresponding upper limit on the level of residual Vero cell DNA for an oral vaccine of 10 mg. As a conservative approach, this empirically determined limit was reduced 100-fold to 100 microg. Thus, the results of this animal study, together with additional evidence in the literature, support a residual DNA safety limit of 100 microg per dose for an oral vaccine produced on a continuous cell line.

[Do we need to relearn abdominal wall closure? : Small stitches]. / Müssen wir den Bauchdeckenverschluss neu erlernen? : Small Stitches.

The 1­year incisional hernia rate of 9-30 % has been tolerated for decades. Even in the 1970s and 1980s there was evidence that supported reducing suture tension. Recently, the traditional 4:1 relationship between suture and wound length, which has been passed on for years, has been questioned. After first experimental and clinical data suggested an advantage by reducing the width and interval of stitches by 50 %, the prospective randomized STITCH study has now provided evidence by significantly lowering the 1­year hernia rate from 21 % to 13 %. For surgeons this means less of a revolution and more of an innovative evolution of a long-established technique. Before introduction of the technique quality assurance must be carried out with documentation of performance indicators (e.g. number of stitches, length of thread incorporated and wound length).

Structure of the ABF1-homologue from Kluyveromyces marxianus.

By transformation of a Saccharomyces cerevisiae mutant strain conditionally expressing the ABF1-gene, a Kluyveromyces marxianus DNA fragment carrying the gene encoding the ABF1-homologue of this yeast strain (KmABF1) was selected. Comparison of the sequence of the KmABF1 gene with that encoding Saccharomyces cerevisiae ABF1 and the previously isolated ABF1-gene from Kluyveromyces lactis (KlABF1) revealed distinct regions displaying considerable homology and therefore most likely representing sequences encoding essential domains. In addition to the domains putatively involved in DNA binding of the protein factor, two short conserved amino acid sequence elements at the C-termini of the homologous proteins were identified, which are proposed to play a part in their trans-acting functions. This is the first report on the structure of a regulatory protein factor from K. marxianus.

P300 in schizophrenia: interactions between amplitudes and topography.

Low P300 amplitudes and topographical asymmetries have been reported in schizophrenic patients, but reference-independent amplitude assessment failed to replicate reduced amplitudes. P300 amplitude is conventially assessed at midline electrodes (Pz), and asymmetric topography as reported in schizophrenics, may confound this measurement. We investigated the possible interaction between P300 topography and assessments of amplitudes. In 41 clinically stable schizophrenics and 31 normal controls, the general finding of reduced amplitudes at the Pz-electrode and topographical asymmetries in the patient group were replicated. In both groups, asymmetries of the P300 field (lateralized peaks) reduced the standard amplitude assessment at the midline parietal electrode, but did not affect the reference-independent, global amplitude assessment. This shows that asymmetry per se does not imply reduced field strength. In addition, in schizophrenics, but not in controls, there was a significant effect of the direction of asymmetry on both amplitude measures, amplitudes being lower with increasing shift of the P300 peak to the right side. Considering also the slightly left-lateralized peaks in the normal controls, this suggests that only right-lateralized P300 peaks express functional deficits in schizophrenics, whereas left-lateralized peaks fall within the physiological variability of the P300 field. The reference-independent amplitude assessment is proposed for unambiguous amplitude assessment in order to better define the clinical, psychological and physiopathological meaning of the P300 alterations in schizophrenics.