Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects.

BACKGROUND: ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer's disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development. OBJECTIVES: To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed. DESIGN: This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2). SETTING: The study was conducted at a First-in-Human unit in Sweden. PARTICIPANTS: Twenty-four healthy male and female subjects. INTERVENTION: The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state. MEASUREMENTS: Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement. RESULTS: Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio. CONCLUSIONS: ACD856 was well tolerated at the tested dose levels (10-90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.

Incidence, detection and outcome of differentiated thyroid cancer in Western Sweden.

BACKGROUND: It is unclear whether the increasing incidence of thyroid cancer (TC) due to increased diagnosis of small and indolent tumours might mask a real increase of clinically significant cancers. The aim of this study was to correlate surgery, pathology and outcome data of individual patients to the mode of primary detection (palpation, by imaging or incidental) to assess if TC incidence has increased. METHODS: The Swedish Cancer Registry identified all patients with TC in Västra Götaland County representing approximately 1.6 million inhabitants. Clinical information was retrieved from medical records of patient cohorts from three study intervals (2001-2002, 2006-2007 and 2011-2014) comprising 60 per cent of all TC patients. Data were also obtained from the NORDCAN registry to compare of TC incidence with other Nordic countries. RESULTS: Between 2001 and 2014, the annualized standard incidence rate/100 000 population (ASR) of TC increased from 3.14 to 10.71 in women and from 1.12 to 3.77 in men. This was higher than the mean incidence for Sweden but similar to that in Norway and Finland. Differentiated TC (DTC) increased more than threefold. The majority of tumours (64 per cent) were detected by palpation. Larger tumours (10-20, 21-40 and greater than 40 mm) increased as much as microcarcinomas (less than 10 mm). Only 5 per cent of the tumours were detected by imaging. All disease-specific deaths (8.5 per cent of DTC in the first two cohorts) and most patients with recurrent or persistent disease (6.6 per cent of DTC cases) were diagnosed due to tumour-related symptoms. CONCLUSION: DTC in Western Sweden gradually increased between 2001 and 2014. The majority of tumours were detected by palpation suggesting a real increase in the incidence of clinically significant thyroid malignancies.

Small intestinal absorption in patients with chronic obstructive pulmonary disease complicated by cor pulmonale - A pilot study.

BACKGROUND: Cor pulmonale is a common complication to Chronic Obstructive Pulmonary Disease (COPD), and may result in increased pressure in the inferior caval vein and stasis of the liver. The chronic pulmonary hypertension may lead to stasis in the veins from the small intestine and thereby compromise absorption of nutrients. AIM: To investigate whether patients with pulmonary hypertension have reduced absorption capacity compared to COPD patients without cor pulmonale. METHODS: Absorption of d-xylose (25 g) and zinc (132 mg), administered as a single dose, was tested in 14 COPD patients, seven with and seven without cor pulmonale. The presence of cor pulmonale was determined by echocardiography. The concentration of d-xylose and zinc were measured in peripheral blood one, two and three hours after ingestion and used as markers of absorption. Furthermore, urine was collected for five hours to determine the amount of excreted d-xylose. RESULTS: No significant difference in absorption of d-xylose (p = 0.28) or zinc (p = 0.51) was found between the two groups. However, a trend towards a delay in d-xylose absorption, as assessed by time-to-peak concentration, was observed in patients with cor pulmonale (p = 0.08). There was no significant difference in the amount of excreted d-xylose in the urine between the groups (p = 0.52). No correlation was found between the tricuspid regurgitation gradient and the absorption of both test-markers (rs = 0.34 and rs = -0.25). Likewise, no correlations were found between the inferior caval pressure during the in- and expiration phases and the absorption of d-xylose (rs = -0.09 rs = 0.23) or zinc (rs = -0.39, rs = -0.39). CONCLUSION: We found no indications that small intestinal absorption is affected in a clinically relevant degree in patients with cor pulmonale.

Subsurface nitrate reduction under wetlands takes place in narrow superficial zones.

This study aims to investigate the depth distribution of the Nitrate Reduction Potential (NRP) on a natural and a re-established wetland. The obtained NRP provides a valuable data of the driving factors affecting denitrification, the Dissimilatory Nitrate Reduction to Ammonium (DNRA) process and the performance of a re-established wetland. Intact soil cores were collected and divided in slices for the determination of Organic Matter (OM) through Loss of Ignition (LOI) as well as Dissolved Organic Carbon (DOC) and NRP spiking nitrate in batch tests. The Nitrate Reduction (NR) was fitted as a pseudo-first order rate constant (k) from where NRPs were obtained. NR took place in a narrow superficial zone showing a dropping natural logarithmic trend along depth. The main driving factor of denitrification, besides depth, was OM. Although, DOC and LOI could not express by themselves and absolute correlation with NRP, high amounts of DOC ensured enough quantity and quality of labile OM for NR. Besides, high concentration of LOI but a scarce abundance of DOC failed to drive NR. DNRA was only important in superficial samples with high contents of OM. Lastly, the high NRP of the re-established wetland confirms that wetlands can be restored satisfactorily.

The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation.

UNLABELLED: ESSENTIALS: The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both in vitro and in vivo. These findings may represent a crossroad between the complement and the coagulation systems. BACKGROUND: The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor in vitro. In vivo studies also show that MASP-1 is involved in thrombogenesis. OBJECTIVES: To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions. METHODS: Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2. RESULTS: Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation. CONCLUSIONS: MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation.

Tagging fast neutrons from an (241)Am/(9)Be source.

Shielding, coincidence, and time-of-flight measurement techniques are employed to tag fast neutrons emitted from an (241)Am/(9)Be source resulting in a continuous polychromatic energy-tagged beam of neutrons with energies up to 7MeV. The measured energy structure of the beam agrees qualitatively with both previous measurements and theoretical calculations.

Cognition and autonomic function in schizophrenia: inferior cognitive test performance in electrodermal and niacin skin flush non-responders.

BACKGROUND: Patients with schizophrenia suffer from a broad range of cognitive disturbances. The impact in terms of functional outcome is significant. There are also several reports of disturbed autonomic regulation in the disease. The present study examined cognitive function as well as psychophysiological parameters in patients with schizophrenia and healthy controls. METHODS: Twenty-five patients and 14 controls were investigated with electrodermal activity (EDA), an oral niacin skin flush test and a comprehensive neurocognitive test program including the Wechsler battery (WAIS-R), Fingertapping Test, Trail Making Test, Verbal Fluency, Benton Visual Retention Test, Wisconsin Card Sorting Test and Rey Auditory Verbal Learning Test. RESULTS: The patients generally had inferior test results compared to controls. Further analysis revealed that the EDA non-responding patient group explained this variation with significant lower test results than controls. On executive tests, EDA non-responders also performed significantly worse than EDA responding patients. The small group of niacin non-responding patients exhibited an even lower overall test performance. Delayed niacin flush also correlated inversely with psychomotor function and IQ in the patients. CONCLUSION: The findings support the hypothesis of a neurodevelopment disturbance affecting both autonomic function and higher cortical function in schizophrenia.

1α,25-dihydroxyvitamin D3 promotes osteogenic activity and downregulates proinflammatory cytokine expression in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: The aim of this study was to assess the impact of 1α,25-dihydroxyvitamin D3 (vitamin D3) on osteogenic and inflammatory properties of human periodontal ligament (PDL) cells and investigate underlying mechanisms. MATERIAL AND METHODS: Human PDL cells, obtained from four subjects, were stimulated with vitamin D3 for 4-48 h. The bone markers osteopontin and osteocalcin and proinflammatory cytokine/chemokine expression was determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Cytokine and chemokine expression was determined after stimulation with the inflammation promoter lipopolysaccharide (LPS) in the presence or absence of vitamin D3. Alkaline phosphatase activity was assessed using p-nitrophenylphosphate substrate. RESULTS: Treatment with 30 ng/mL of vitamin D3, corresponding to an optimal plasma concentration of vitamin D, for 24 h had no effect on PDL cell number and morphology but increased PDL cell osteopontin and osteocalcin mRNA expression by about 70 and 40%, respectively, and, moreover, treatment with vitamin D3 for 48 h enhanced PDL cell alkaline phosphatase activity by about two times showing that vitamin D3 exerts pro-osteogenic effects in human PDL cells. Stimulation with LPS (1 µg/mL) for 4 h increased PDL cell interleukin (IL)-6 cytokine and chemokine ligand 1 (CXCL1) chemokine mRNA expression several fold. The LPS-induced increase in IL-6 and CXCL1 transcripts was attenuated by vitamin D3 (30 ng/mL). Treatment with vitamin D3 (3-300 ng/mL) for 24 h reduced the LPS-evoked increase in PDL cell IL-6 protein by about 50%. Vitamin D3 (30 ng/mL) had no effect on LPS-induced IL-1ß and MCP-1 mRNA expression. CONCLUSIONS: Vitamin D3 promotes osteogenic differentiation but also downregulates inflammation promoter-induced IL-6 cytokine and CXCL1 chemokine expression in human PDL cells, suggesting that vitamin D3 both stimulates bone regeneration and antagonizes inflammation in human periodontal tissue.

Human endogenous peptide p33 inhibits detrimental effects of LL-37 on osteoblast viability.

BACKGROUND AND OBJECTIVE: High levels of the antimicrobial peptide, LL-37, are detected in gingival crevicular fluid from patients with chronic periodontitis. LL-37 not only shows antimicrobial activity but also affects host-cell viability. The objective of the present study was to identify endogenous mechanisms that antagonize the detrimental effects of LL-37 on osteoblast viability, focusing on the human peptide p33 expressed on the surface of various cell types. MATERIAL AND METHODS: Human osteoblast-like MG63 cells and human hFOB1.19 osteoblasts were treated with or without LL-37 in the presence or absence of p33. Recombinant human p33 was expressed in an Escherichia coli expression system. Lactate dehydrogenase (LDH) was assessed using an enzymatic spectrophotometric assay. DNA synthesis was determined by measuring [(3) H]-thymidine incorporation. Cell number was assessed by counting cells in a Bürker chamber. Intracellular Ca(2+) was monitored by recording Fluo 4-AM fluorescence using a laser scanning confocal microscope. Cellular expression of p33 was determined by western blotting. RESULTS: LL-37 caused a concentration-dependent release of LDH from human osteoblasts, showing a half-maximal response value (EC50 ) of 4 µm and a rapid and sustained rise in the intracellular Ca(2+) concentration of osteoblasts, suggesting that LL-37 forms pores in the cell membrane. p33 (10 µm) inhibited the LL-37-induced LDH release and LL-37-evoked rise in intracellular Ca(2+) concentration, suggesting that p33 prevents LL-37-induced permeabilization of the cell membrane. Moreover, p33 blocked LL-37-induced attenuation of osteoblast numbers. Also, mucin antagonized, at concentrations representative for nonstimulated whole saliva, LL-37-evoked LDH release, whilst cationic endogenous polyamines had no impact on LL-37-induced LDH release from osteoblasts. CONCLUSIONS: The endogenous peptide p33 prevents LL-37-induced reduction of human osteoblast viability. Importantly, this mechanism may protect the osteoblasts from LL-37-induced cell damage in patients suffering from chronic periodontitis associated with high levels of LL-37 locally.

Platelet count and function in paediatric cardiac surgery: a prospective observational study.

BACKGROUND: Platelet deficiency, impaired platelet function, or both increase the risk of bleeding complications. We assessed platelet count and function during and after paediatric cardiac surgery. Secondary aims included the effect of modified ultrafiltration, identification of factors associated with platelet dysfunction, and to assess associations between platelet function and transfusion requirements. METHODS: Fifty-seven patients were included in a prospective observational study. Platelet count and platelet function (multiple-electrode impedance aggregometry) were analysed before and during cardiopulmonary bypass (CPB), after modified ultrafiltration, on arrival at the intensive care unit, and on the first postoperative day. Intraoperative transfusions of blood products were registered. RESULTS: Both platelet count and platelet aggregation were markedly reduced during surgery with the greatest reduction at the end of CPB. On postoperative day 1, platelet count was still reduced by 50%, while platelet aggregation had returned to-or above-preoperative levels. There were only moderate correlations between platelet count and platelet aggregation. Modified ultrafiltration had no significant influence on platelet count or aggregation. Young age, low weight, and long operation time were associated with poor platelet aggregation during surgery, while young age, low weight, high preoperative haemoglobin levels, and low preoperative platelet count were associated with poor aggregation after operation. Patients with impaired platelet function during CPB had markedly increased intraoperative transfusion requirements. CONCLUSIONS: Platelet count and platelet aggregation are markedly reduced during and immediately after paediatric cardiac surgery, especially in neonates. The recovery in aggregation is faster than that in platelet count. Intraoperative platelet dysfunction is associated with increased transfusion requirements.

Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy.

B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.

Work health determinants in employees without sickness absence.

BACKGROUND: Working ability is known to be related to good physical condition, clear work tasks, positive feedback and other occupational, organizational and psychosocial factors. In Sweden, high levels of sickness absence are due to stress-related disorders and musculoskeletal pain. AIMS: To identify work health characteristics in a working population with a large variety of professional skills and occupational tasks. METHODS: Employers' data on occupation, sickness absence, age and gender in a working population of 11 occupational groups and questionnaire responses regarding work-organization, environment, work stress, pain, health, and socio-demographic factors were collected. Employees with no history of sick-leave were compared with those with a history of sick-leave (1-182 days, mean 25 days). RESULTS: Of 2641 employees, 1961 participated. Those with no history of sick-leave reported less work-related pain, work-related stress, sleep disturbances, worry about their health, 'sick-presenteeism', monotonous work, bent and twisted working positions and exposure to disturbing noise than those with a history of sick-leave (P < 0.001). They also reported better health, support from superiors, having influence on their working hours and evening and week-end working, longer working hours per week (P < 0.001) and more regular physical training (P < 0.01). Socio-demographic factors were less important than gender, and differences in responses between occupational groups were also found. CONCLUSIONS: Workers without a history of sick-leave experienced less stress, sleep disturbances, worry about their own health and less neck, shoulder and back pain and more support from their superiors and influence on their working hours.

The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study.

The Swedish OCTO and NONA immune longitudinal studies were able to identify and confirm an immune risk profile (IRP) predictive of an increased 2-year mortality in very old individuals, 86-94 years of age. The IRP, was associated with persistent cytomegalovirus infection and characterized by inverted CD4/CD8 ratio and related to expansion of terminally differentiated effector memory T cells (TEMRA phenotype). In the present HEXA immune longitudinal study, we have examined a younger group of elderly individuals (n = 424, 66 years of age) in a population-based sample in the community of Jönköping, Sweden, to examine the relevance of findings previously demonstrated in the very old. Immunological monitoring that was conducted included T cell subsets and CMV-IgG and CMV-IgM serology. The result showed a prevalence of 15 % of individuals with an inverted CD4/CD8 ratio, which was associated with seropositivity to cytomegalovirus and increases in the level of TEMRA cells. The proportion of individuals with an inverted CD4/CD8 ratio was significantly higher in men whereas the numbers of CD3+CD4+ cells were significantly higher in women. In conclusion, these findings are very similar to those previously found by us in the Swedish longitudinal studies, suggesting that an immune profile previously identified in the very old also exists in the present sample of hexagenerians. Therefore, it will be important to examine clinical parameters, including morbidity and mortality, to assess whether the immune profile also is a risk profile associated with higher mortality in this sample of hexagenerians.

Nanoplasma dynamics of single large xenon clusters irradiated with superintense x-ray pulses from the linac coherent light source free-electron laser.

The plasma dynamics of single mesoscopic Xe particles irradiated with intense femtosecond x-ray pulses exceeding 10(16) W/cm2 from the Linac Coherent Light Source free-electron laser are investigated. Simultaneous recording of diffraction patterns and ion spectra allows eliminating the influence of the laser focal volume intensity and particle size distribution. The data show that for clusters illuminated with intense x-ray pulses, highly charged ionization fragments in a narrow distribution are created and that the nanoplasma recombination is efficiently suppressed.

The antimicrobial peptide LL-37 is anti-inflammatory and proapoptotic in human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: The antimicrobial peptide LL-37 is expressed in periodontal tissue, and variations in LL-37 levels have been associated with periodontal disease. The effects of LL-37 on periodontal ligament cell function have not been described before. Here, we assess anti-inflammatory properties of LL-37 and investigate the effects of LL-37 on cell differentiation, cell proliferation and apoptosis in human periodontal ligament cells. MATERIAL AND METHODS: Periodontal ligament cells were obtained from teeth extracted for orthodontic reasons. Cytokine (interleukin-6) and chemokine (monocyte chemoattractant protein-1) expression was determined by quantitative PCR, cell differentiation by alkaline phosphatase activity, cell proliferation by counting cells in a Bürker chamber, DNA synthesis by incorporation of radiolabeled thymidine and apoptosis by cell morphology and activated caspase 3 quantities. RESULTS: Treatment with 0.1 and 1 µm of LL-37 totally reversed lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and suppressed lipopolysaccharide-induced interleukin-6 expression by 50-70%. LL-37 had no effect on alkaline phosphatase activity. Incubation with 8 µm LL-37 strongly reduced cell number. DNA synthesis was attenuated by about 90% in response to 8 µm LL-37, confirming its antiproliferative effect. Cell morphology was altered in an apoptosis-like fashion in cells treated with 8 µm LL-37. Furthermore, the quantity of activated caspase 3 was increased in cells treated with 1 and 8 µm of LL-37, suggesting apoptosis. CONCLUSION: LL-37 strongly attenuates lipopolysaccharide-induced cytokine and chemokine expression and, in high concentrations, reduces cell proliferation through inhibition of DNA synthesis and by promoting apoptosis in human periodontal ligament cells.

Physical capacity, respiratory quotient and energy expenditure during exercise in male patients with schizophrenia compared with healthy controls.

BACKGROUND: Despite massive research on weight gain and metabolic complications in schizophrenia there are few studies on energy expenditure and no current data on physical capacity. AIM: To determine oxygen uptake capacity, respiratory quotient (RQ) and energy expenditure during a submaximal exercise test in patients with schizophrenia and healthy controls. METHOD: Ten male patients and 10 controls were included. RQ and energy expenditure were investigated with indirect calorimetry during a cycle ergometer test. The submaximal work level was defined by heart rate and perceived exhaustion. Physical capacity was determined from predicted maximal oxygen uptake capacity (VO(2-max)). RESULTS: The patients exhibited significantly higher RQ on submaximal workloads and lower physical capacity. A significant lower calculated VO(2-max) remained after correction for body weight and fat free mass (FFM). Energy expenditure did not differ on fixed workloads. CONCLUSION: RQ was rapidly increasing in the patients during exercise indicating a faster transition to carbohydrate oxidation and anaerobic metabolism that also implies a performance closer to maximal oxygen uptake even at submaximal loads. This may restrict the capacity for everyday activity and exercise and thus contribute to the risk for weight gain. Physical capacity was consequently significantly lower in the patients.

Complement activation products in liquid stored plasma and C3a kinetics after transfusion of autologous plasma.

BACKGROUND AND OBJECTIVES: Keeping a small stock of liquid plasma readily available for transfusion is common practise in Sweden. We report data on complement activation markers in plasma components during storage in the liquid state and the kinetics of C3a-(desArg) after transfusion of autologous plasma with high content of C3a-(desArg). MATERIAL AND METHODS: Plasma components were prepared by apheresis or from whole blood. C3 fragments (C3a-(desArg), C3d,g, iC3), and soluble terminal complement complex (sC5b-9) were investigated. C3a-(desArg) kinetics was investigated in regular apheresis donors. RESULTS: Apheresis plasma prepared by membrane centrifugation had significantly higher level of C3a-(desArg), C3d,g and sC5b-9 from day 0 and low iC3, than plasma prepared by other methods. By storage day 7, C3a-(desArg)-levels were above the reference value in 88% of all components. After re-infusion of autologous plasma with high C3a-(desArg) content, there were rapid a(1) and a(2)-distribution followed by a slower b-elimination phase. CONCLUSION: Plasma components prepared by different methods and stored in the liquid phase differ significantly in the amount and timing of complement activation. C3a-(desArg) present in plasma is rapidly eliminated after transfusion. Autologous plasma could be used to study complement kinetics in different clinical situations.

Complement activation during liver transplantation-special emphasis on patients with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected.