Are serum autoantibodies associated with brain changes in systemic lupus erythematosus? MRI data from the Leiden NP-SLE cohort.

OBJECTIVE: The effect of serum autoantibodies on the brain of systemic lupus erythematosus (SLE) patients remains unclear. We investigated whether serum autoantibodies, individually and assessed in groups, are associated with specific brain-MRI abnormalities or whether these structural changes are associated with other SLE-related or traditional cardiovascular disease risk factors. METHODS: All patients underwent brain 3Tesla-MRI. White matter hyperintensities (WMHs), ischemic lesions, inflammatory-like lesions and cerebral atrophy were scored. Serum autoantibodies analyzed included lupus anticoagulant (LAC), anticardiolipine (aCL) IgG and IgM (first 3 also grouped into antiphospholipid autoantibodies (aPL)), anti-dsDNA, anti-SSA, anti-SSB, anti-RNP, and anti-Sm (the latter 5 grouped into SLE-related autoantibodies). Associations were assessed using logistic regression analysis adjusted for potential confounders. Furthermore, a sensitivity analysis including anti-Beta2 glycoprotein-1 antibodies (anti-ß2GP1) in the aPL group was performed and the potential modification role of the neuropsychiatric clinical status in the model was assessed. RESULTS: 325 patients (mean age 42 years (SD 14), 89% female) were included. The following MRI-brain abnormalities were found: WMHs (71%), lacunar infarcts (21%), gliosis (11%), micro-hemorrhages (5%), large hemorrhages (2%), inflammatory-like lesions (6%) and atrophy (14%). No associations were found between individual or total SLE-related autoantibodies and inflammatory-like lesions. A higher number of positive aPL was associated with lacunar infarcts (OR 1.37 (95%CI 1.02-1.99) and gliosis (OR 2.15 (1.37-3.37)). LAC was associated with lacunar infarcts in white matter (OR 3.38 (1.32-8.68)) and atrophy (OR 2.49 (1.01-6.15)), and aCL IgG with gliosis (OR 2.71 (1.05-7.02)). Among other variables, SLE patients with hypertension presented a higher chance for WMHs (OR 5.61 (2.52-12.48)) and lacunar infarcts in WM (OR 2.52 (1.10-5.74)) and basal ganglia (OR 8.34 (2.19-31.70)), while cumulative SLE-damage was correlated with lacunar infarcts in WM (OR 1.43 (1.07-1.90)), basal ganglia (OR 1.72 (1.18-2.51)) and cerebellum (OR 1.79 (1.33-2.41)). These associations were confirmed in the sensitivity analysis. CONCLUSIONS: Brain abnormalities in SLE represent different underlying pathogenic mechanisms. aPL are associated with ischemic brain changes in SLE, while the presence of SLE-related serum autoantibodies is not related to inflammatory-like lesions. Hypertension and cumulative SLE-damage associate with ischemic MRI-brain changes in SLE, suggesting the importance of accelerated atherosclerosis in this process.

Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up.

OBJECTIVES: To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. METHODS: Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. RESULTS: PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. DISCUSSION AND CONCLUSION: The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

Time-efficient measurement of multi-phase arterial spin labeling MR signal in white matter.

White matter (WM) perfusion has great potential as a physiological biomarker in many neurological diseases. Although it has been demonstrated previously that arterial spin labeling magnetic resonance imaging (ASL-MRI) enables the detection of the perfusion-weighted signal in most voxels in WM, studies of cerebral blood flow (CBF) in WM by ASL-MRI are relatively scarce because of its particular challenges, such as significantly lower perfusion and longer arterial transit times relative to gray matter (GM). Recently, ASL with a spectroscopic readout has been proposed to enhance the sensitivity for the measurement of WM perfusion. However, this approach suffers from long acquisition times, especially when acquiring multi-phase ASL datasets to improve CBF quantification. Furthermore, the potential increase in the signal-to-noise ratio (SNR) by spectroscopic readout compared with echo planar imaging (EPI) readout has not been proven experimentally. In this study, we propose the use of time-encoded pseudo-continuous ASL (te-pCASL) with single-voxel point-resolved spectroscopy (PRESS) readout to quantify WM cerebral perfusion in a more time-efficient manner. Results are compared with te-pCASL with a conventional EPI readout for both WM and GM perfusion measurements. Perfusion measurements by te-pCASL PRESS and conventional EPI showed no significant difference for quantitative WM CBF values (Student's t-test, p = 0.19) or temporal SNR (p = 0.33 and p = 0.81 for GM and WM, respectively), whereas GM CBF values (p = 0.016) were higher using PRESS than EPI readout. WM CBF values were found to be 18.2 ± 7.6 mL/100 g/min (PRESS) and 12.5 ± 5.5 mL/100 g/min (EPI), whereas GM CBF values were found to be 77.1 ± 11.2 mL/100 g/min (PRESS) and 53.6 ± 9.6 mL/100 g/min (EPI). This study demonstrates the feasibility of te-pCASL PRESS for the quantification of WM perfusion changes in a highly time-efficient manner, but it does not result in improved temporal SNR, as does traditional te-pCASL EPI, which remains the preferred option because of its flexibility in use.

Prioritizing point-based POMDP solvers.

Recent scaling up of partially observable Markov decision process (POMDP) solvers toward realistic applications is largely due to point-based methods that quickly converge to an approximate solution for medium-sized domains. These algorithms compute a value function for a finite reachable set of belief points, using backup operations. Point-based algorithms differ on the selection of the set of belief points and on the order by which backup operations are executed on the selected belief points. We first show how current algorithms execute a large number of backups that can be removed without reducing the quality of the value function. We demonstrate that the ordering of backup operations on a predefined set of belief points is important. In the simpler domain of MDP solvers, prioritizing the order of equivalent backup operations on states is known to speed up convergence. We generalize the notion of prioritized backups to the POMDP framework, showing how existing algorithms can be improved by prioritizing backups. We also present a new algorithm, which is the prioritized value iteration, and show empirically that it outperforms current point-based algorithms. Finally, a new empirical evaluation measure (in addition to the standard runtime comparison), which is based on the number of atomic operations and the number of belief points, is proposed in order to provide more accurate benchmark comparisons.

A simplifier for propositional formulas with many binary clauses.

Deciding whether a propositional formula in conjunctive normal form is satisfiable (SAT) is an NP-complete problem. The problem becomes linear when the formula contains binary clauses only. Interestingly, the reduction to SAT of a number of well-known and important problems--such as classical AI planning and automatic test pattern generation for circuits--yields formulas containing many binary clauses. In this paper we introduce and experiment with 2-SIMPLIFY, a formula simplifier targeted at such problems. 2-SIMPLIFY constructs the transitive closure of the implication graph corresponding to the binary clauses in the formula and uses this graph to deduce new unit literals. The deduced literals are used to simplify the formula and update the graph, and so on, until stabilization. Finally, we use the graph to construct an equivalent, simpler set of binary clauses. Experimental evaluation of this simplifier on a number of bench-mark formulas produced by encoding AI planning problems prove 2-SIMPLIFY to be a useful tool in many circumstances.

Measurement of intravascular Na(+) during increased CBF using (23)Na NMR with a shift reagent.

Sodium ions are intimately involved with neural activity. Thus, it is highly desirable to devise a way of mapping brain activity via sodium imaging. Sodium ions exist in the extravascular and intravascular spaces. To separate the two components, the shift reagent Tm(DOTP)(5-) was intravenously introduced into rats. Intravascular sodium changes in the rat brain were measured during increased blood flow induced by hypercapnia using volume-localized (23)Na-NMR. The intravascular sodium changes, equivalent to cerebral blood volume changes, are significant during hypercapnia conditions and correlate well with the increase in arterial pCO(2). This suggests that the intravascular sodium change is dominant in total (23)Na spectroscopy or imaging of the brain during blood flow increase induced by external perturbation.

Management of severe hypokalemia in hospitalized patients: a study of quality of care based on computerized databases.

BACKGROUND: While administrative databases are used to assess general indicators of quality of care, a detailed audit of the process of clinical care usually requires review of hospital medical records. OBJECTIVE: To evaluate the feasibility of assessing the management of severe hypokalemia using computerized administrative and laboratory databases. METHODS: The study included all patients hospitalized in 1997 who experienced serum potassium levels of less than 3.0 mmol/L at Hadassah University Hospital, Jerusalem, Israel, a tertiary care center. Using the computerized databases, we measured the following: (1) whether a subsequent serum potassium test was performed, (2) time to the subsequent test and to normalization of the serum potassium level, (3) achievement of normokalemia, and (4) in-hospital mortality. In a random subsample of 100 patients, these measures were compared with the blinded assessment of the quality of medical management of hypokalemia, as determined from medical records, using predetermined criteria for adequate management. RESULTS: The computerized databases revealed that severe hypokalemia occurred in 866 patients (2.6% of the yearly hospitalizations): 55 patients (6.4%) had no subsequent serum potassium levels measured, and 260 (30.0%) were discharged from the hospital with a subnormal potassium level. The mean time to a subsequent test was 20 hours, and to normokalemia, 50 hours; both intervals varied by department. In-hospital mortality was 20.4%, or 10-fold that of the entire hospitalized population. A review of hospital medical records revealed inadequate clinical management of hypokalemia in 24%, which was associated with nonperformance of a subsequent test (likelihood ratio, 8.4), failure to normalize the serum potassium level (likelihood ratio, 4.2), discharge from the hospital with a subnormal potassium level (likelihood ratio, 2.1), and in-hospital death (likelihood ratio, 2.5), all of which could be determined by the computerized databases. CONCLUSIONS: The computerized laboratory database is useful in ascertaining the prevalence of severe hypokalemia and in assessing shortcomings in its management. Databases can be used to derive valid and efficient measures of the quality of the clinical management of electrolyte disorders.

The contribution of multiple data sources to a clinical audit of lymphoma in a teaching hospital.

OBJECTIVE: To assess the independent contribution of data sources used for case ascertainment in a clinical audit of the outcome of lymphoma patients in our institution. DESIGN: In the absence of a unified register of lymphoma patients diagnosed and/or treated in our institution, we used an elective approach to case ascertainment. Sources included two internal databases (computerized discharge data for hospitalizations and outpatient oncology database) and one external (Israel Cancer Registry) database. Histologic diagnosis was confirmed by search of on-line pathology files or discharge summaries. Demographic, histologic and survival characteristics were compared among patients identified through each data source. Survival was assessed via record linkage with the Population Registry. SETTING: A tertiary care university teaching hospital. STUDY PARTICIPANTS: Seven hundred and twelve patients with lymphoma diagnosed between 1987 and 1992. RESULTS: All three sources contributed independently to the total, with the majority (583 or 82%) via hospitalizations. Overlap among the sources was minimal with only 73 (10.3%) of the patients being common to all three sources. Differences (P < 0.05) in the age distribution, country of birth and population groups (defined by religion) as well as histologic diagnoses among the sources were noted. In addition, survival of those ascertained via the outpatient database was higher than those ascertained from other sources (P=0.02 for Hodgkin's disease) even after controlling for age. CONCLUSIONS: The use of multiple data sources for case ascertainment in clinical audit is justified when no patient register exists. The results indicate that use of a single internal data source would have resulted both in an underestimate of the scope of lymphoma in our institution and significant bias in terms of patient characteristics and outcome.

Imaging of H217O distribution in the brain of a live rat by using proton-detected 17O MRI.

Imaging of H217O has a number of important applications. Mapping the distribution of H217O produced by oxidative metabolism of 17O-enriched oxygen gas may lead to a new method of metabolic functional imaging; regional cerebral blood flow also can be measured by measuring the H217O distribution after the injection of 17O-enriched physiological saline solution. Previous studies have proposed a method for indirect detection of 17O. The method is based on the shortening of the proton T2 in H217O solutions, caused by the residual 17O-1H scalar coupling and transferred to the bulk water via fast chemical exchange. It has been shown that the proton T2 of H217O solutions can be restored to that of H216O by irradiating the resonance frequency of the 17O nucleus. The indirect 17O image thus is obtained by taking the difference between two T2-weighted spin-echo images: one acquired after irradiation of the 17O resonance and one acquired without irradiation. It also has been established that, at relatively low concentrations of H217O, the indirect method yields an image that quantitatively reflects the H217O distribution in the sample. The method is referred to as PRIMO (proton imaging of oxygen). In this work, we show in vivo proton images of the H217O distribution in a rat brain after an i.v. injection of H217O-enriched physiological saline solution. Implementing the indirect detection method in an echo-planar imaging sequence enabled obtaining H217O images with good spatial and temporal resolution of few seconds.

Two-way referral bias: evidence from a clinical audit of lymphoma in a teaching hospital.

The objective of this study was to evaluate the effect of referral bias in a clinical audit of lymphoma in a university hospital. We compared demographic and clinical characteristics as well as survival for Jerusalem residents (local) and referred (distant) patients diagnosed from 1987 to 1992 and treated in our institution. Referred patients were younger (p < 0.0001), and less likely to be immigrants (p < 0.0001), than local patients. Aggressive non-Hodgkin's lymphomas (NHL) were more common in the referred population (p = 0.015). Survival for Hodgkin's disease was consistently better for local patients, but for patients with NHL the findings were reversed. In this study referred patients differed in their clinical and sociodemographic characteristics but did not consistently exhibit a worse outcome than that of local patients. The unpredictable nature of referral bias may be due to better functional status or resources among referred patients, or to selective referral for procedures such as bone marrow transplantation. While reports on the natural history of disease from tertiary institutions may be biased by referral patterns, the direction of the bias is not uniform.

Imaging H2(17)O distribution in a phantom and measurement of metabolically produced H2(17)O in live mice by proton NMR.

Previously we suggested a method for indirect detection of H2(17)O via a combination of 1H spin-echo sequence and 17O decoupling. The method is based on the shortening of the water proton T2 due to the residual spin-spin coupling with the 17O nucleus, and on our finding that this shortening is abolished by applying an radio frequency field at the 17O resonance frequency. In the present work we demonstrate how the method can be used for imaging low concentrations of H2(17)O, and report for the first time an application of this method to in vivo detection of H2(17)O in live newborn mice, where the H2(17)O was introduced either directly i.p. or by inhalation of 17O2 where it was formed by oxidative metabolic activity.

Ethical dilemmas experienced by hospital and community nurses: an Israeli survey.

The objective of this survey was to assess the extent to which nurses encounter and identify dilemma-generating situations in the light of the publication and circulation of the Israeli code of ethics for nurses in 1994. The results are being used as a basis for a programme aimed at promoting nurses' decision-making skills in coping with ethical dilemmas. In this era of major advances in medicine, the nurse's role as the protector of patient rights may bring about conflicts with physicians' orders, with institutional policies, or with patients' families. Nurses will then become confronted with ethical and moral dilemmas. A nationwide survey was carried out to identify and describe the ethical conflicts with which nurses in Israel are confronted in the course of their work. A third of the enumerated dilemmas were encountered by more than 50% of the nurses. The major determinant influencing encounters with dilemmas, as perceived by the participating nurses, was their work setting, namely, the hospital versus the community. It was shown that nurses seek support mainly among their peers, they are barely familiar with the Israeli Code, and they consider their own families as the predominant factor in shaping their ethical attitudes.

Professional evacuation of persons injured in road accidents in Israel is fast but underused.

In a study of the evacuation process of injured people from motor vehicle accidents, 2,206 injured evacuees were interviewed in five emergency rooms in Israel. Of these, only 53% were evacuated professionally (by ambulance or helicopter), and only 75% arrived directly to an emergency room. In a logistic regression analysis, differences were found in relation to regions, type of road (urban vs. interurban), education, and severity of the injury. Higher education was associated with lower percentage of professional evacuation. Of those injured who arrived directly at emergency rooms, 67% did so within an hour (the "golden hour"). We found that professional evacuation was more rapid than nonprofessional evacuation.

A new method for proton detection of H2(17)O with potential applications for functional MRI.

A method is presented for the sensitive detection of minute amounts of H2(17)O. The method is based on the increase of the T2 of the water protons following an irradiation of the 17O resonance frequency, due to the partial or full decoupling of the 1H-17O spin-spin interaction. It is demonstrated that when 17O concentrations are low, full decoupling is achieved, and at short echo times the increase in the amplitude of the proton echo signal is proportional to the 17O content of the sample. The potential of the method for indirect 17O imaging is substantiated by a simple one dimensional projection of cylindrical phantoms containing various 17O concentrations. Using interleaved sequences with and without 17O decoupling, errors due to time dependent effects are minimized.

Alpha interferon has no effect on lidocaine metabolism in the rat.

Interferons (IFN) inhibit activity of many isoenzymes of the hepatic microsomal cytochrome P-450 system. This inhibition is species specific. Lidocaine is metabolized by cytochrome P-450 III A 4. We investigated in the rat the effect of rat alpha-IFN on lidocaine elimination and on its extraction by the isolated perfused rat liver. To determine elimination, the femoral artery and vein were cannulated. 24 h later, the conscious rat was given lidocaine through the venous catheter and blood was drawn from the arterial catheter for lidocaine determination every 3 min for 20 min. 7 rats were pre-treated with intramuscular rat alpha-IFN 7.5 x 10(5) U, 24 h prior to the experiment and another 4 rats were given saline i.m. The lidocaine elimination rate constant was unchanged, 0.065 min-1 and 0.063 min-1 for the control and IFN groups, respectively. To investigate lidocaine extraction, the isolated perfused rat liver was used. Perfusate samples from the portal and hepatic veins were drawn at 2 min intervals for 20 min, and lidocaine extraction determined. Extraction was determined in two groups of 6 rats each. The first group served as control and these rats were injected with saline only, while in the second group, the rats were pre-treated with rat alpha-IFN 7.5 x 10(5) U. Lidocaine extraction by the isolated perfused rat liver remained unchanged, 97.0 +/- 0.7% and 94.0 +/- 2.4% in the control and IFN treated groups, respectively. It is concluded that the rat alpha-IFN affects neither the elimination nor the extraction of lidocaine.

Cimetidine and omeprazole do not affect cyclosporine disposition by the rat liver.

Cyclosporine has been used with increased frequency, occasionally in conjunction with cimetidine and omeprazole. The present study was undertaken to study a possible interaction between either of the two drugs and cyclosporine in the liver. The isolated perfused rat liver was used with recirculation of perfusate for 150 min. 6 experiments were performed with each of the following: cyclosporine alone, cyclosporine with cimetidine, and cyclosporine with omeprazole. Initial concentrations of cyclosporine, cimetidine and omeprazole were 600 micrograms/ml, 12.5 micrograms/ml, and 4.5 micrograms/ml, respectively. At 1 and 2 h of perfusion 1 micrograms of omeprazole was added to perfusate. Cyclosporine concentration was determined at 30 min intervals. Results at 150 min expressed as percentage of the initial concentration of cyclosporine were 59 +/- 3%, 55 +/- 6%, and 60 +/- 9% for cyclosporine alone, with cimetidine and with omeprazole, respectively. The elimination rate of cyclosporine by the liver did not change during the entire experiment with the addition of cimetidine or omeprazole. Thus, it is concluded that short administration of cimetidine or omeprazole will not affect cyclosporine metabolism by the liver.

Recovery of hepatic clearance and extraction following a release of common bile duct obstruction in the rat.

The rate of recovery for hepatic clearance and extraction following release of common-duct obstruction was investigated in the rat. Male Wistar rats underwent ligation of a cannulated common bile duct. Two weeks later, the cannula was opened and implanted into the duodenum, thus re-establishing enterohepatic circulation. Hepatic extraction and indocyanine green clearance were determined in three groups of six rats each, which differed by the time elapsed from the re-establishment of communication between the common bile duct and duodenum, i.e., 1, 48 and 168 h, respectively. A fourth group, in which a sham operation was performed, served as a control. Clearance was reduced from 16.9 +/- 2.5 ml/min per kg in the control group to 2.9 +/- 0.8, 5.4 +/- 2.4, and 8.5 +/- 3.3 ml/min per kg 1, 48, and 168 h, respectively, after release of common-bile-duct obstruction. Extraction rate was reduced from 37.3 +/- 5.9% to 17.5 +/- 2.7% in the 1st hour and recovered completely at 1 week. Thus, in the rat, release of a 2-week common-bile-duct obstruction is associated with complete recovery of the extraction capacity of the liver within a week, but only incomplete recovery of clearance. This decrease in clearance seems to be due to a decrease in effective hepatic blood flow, mostly probably due to the development of porto-systemic shunts.

Bile acid synthesis from HDL cholesterol and cholesterol ester by cultured chick embryo hepatocytes.

A comparison of the uptake and conversion of HDL cholesterol and cholesterol ester to bile acids by chick embryo hepatocytes showed the following. Considerable amounts of cholesterol but not cholesterol ester accumulated in the cells. Cholesterol ester was hydrolyzed to cholesterol, 60% of which was converted to bile acids. Approximately 3-5-times more cholesterol ester than cholesterol were converted to bile acids. The degradation of 125I-labelled HDL by the hepatocytes was negligible. Chloroquine did not inhibit the conversion of HDL cholesterol and cholesterol ester to bile acids. HDL stimulated the conversion of [14C]mevalonolactone to cholesterol, the greater part of which was found in the medium. Its conversion to bile acids was not affected. The cholesterol pool of hepatocytes was labelled by preincubation with [14C]mevalonolactone. Upon addition of 3H-labelled HDL cholesterol, cholesterol efflux and influx were measured simultaneously. Both processes were dependent on HDL concentration and time of incubation. Efflux exceeded influx, drawing upon the cholesterol and cholesterol ester reserves of the cell. Bile acids were formed simultaneously from the prelabelled [14C]cholesterol pool and the exogenously added 3H-labelled HDL cholesterol.