Morphological abnormalities in nitric-oxide-synthase-positive striatal interneurons of schizophrenic patients

Schizophrenia has been suggested to be a neurodevelopmental disorder, and nitric-oxide-synthase (NOS)-positive neurons were shown to be involved in distorted cortical development in schizophrenia. Here we investigated whether nitrinergic neurons in the striatum of schizophrenic patients also display abnormalities regarding distribution or morphology. To do so, postmortem putaminal sections of schizophrenic subjects were examined by means of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) staining and NOS immunohistochemistry. NOS-positive neurons were counted and analyzed morphologically. Abnormalities regarding morphology or number of NOS-containing neurons could be found in the putamen of schizophrenics (n = 3), but not controls (n = 5). Neurons were either of abnormal size and branching pattern, or they were markedly reduced (130 +/- 44 vs. 54 +/- 62 NADPHd-positive somata/mm(3) putamen; p < 0.0001). Striatal nitrinergic interneurons might thus be involved in the pathogenesis of at least some forms of schizophrenia. Studies on larger samples are however needed to further corroborate this finding.     

Numerical modeling of needle tip artifacts in MR gradient echo imaging

Exact determination of needle tip position is obsolete for interventional procedures under control of magnetic resonance imaging (MRI). Exact needle tip navigation is complicated by the paramagnetism of microsurgical instruments: Local magnetic field inhomogeneities are induced resulting in position encoding artifacts and in signal voids in the surrounding of instruments and especially near their tips. The artifacts generated by the susceptibility of the material are not only dependent on the material properties themselves and on the applied MRI sequences and parameters, but also on the geometric shape of the instruments and on the orientation to the static magnetic field in the MR unit. A numerical model based on superposition of induced elementary dipole fields was developed for studying the field distortions near paramagnetic needle tips. The model was validated by comparison with experimental data using field mapping MRI techniques. Comparison between experimental data and numerical simulations revealed good correspondence for the induced field inhomogeneities. Further systematic numerical studies of the field distribution were performed for variable types of concentric and asymmetric tip shapes, for different ratios between tip length and needle diameter, and for different orientations of the needle axis in the external static magnetic field. Based on the computed local inhomogeneities of the magnetic field in the surroundings of the needle tips, signal voids in usual gradient echo images were simulated for a prediction of the artifacts. The practically relevant spatial relation between those artifacts and the hidden tip of the needle was calculated for the different tip shapes and orientations in the external field. As needle tip determination is crucial in interventional procedures, e.g., in taking biopsies, the present model can help to instruct the physician prior to surgical interventions in better estimating the needle tip position for different orientations and needle tip shapes as they appear in interventional procedures. As manufacturing prototypes with subsequent measurements of artifacts in MRI are a costly procedure the presented model may also help to optimize shapes of needle tips and of other parts of MR-compatible instruments and implants with low expense prior to production if some shape parameters can be chosen freely.     

Autoimmune lymphoproliferative syndrome: a cause of chronic splenomegaly, lymphadenopathy, and cytopenias in children-report on diagnosis and management of five patients

Autoimmune lymphoproliferative syndrome (ALPS) usually manifests in early childhood with splenomegaly, lymphadenopathy, and cytopenias. In most patients, it results from mutations in genes that regulate lymphocyte apoptosis via the Fas pathway. Here, we report five children with ALPS. All five children had splenomegaly, cytopenias, and hypertriglyceridemia at presentation; four had lymphadenopathy. Mutations in the Fas receptor gene were demonstrated in three children. Clinical picture is variable: in only one child manifestations are severe enough to require immunosuppressive therapy. Diagnosis of ALPS can be challenging and increased awareness of the disease can result in more directed diagnostic approaches as well as earlier initiation of treatment.     

Modulation of hypoxic pulmonary vasoconstriction is time and nitric oxide dependent in a peritonitis model of sepsis

Objective This study assessed modulation of hypoxic pulmonary vasoconstriction (HPV) in isolated perfused rat lungs during sepsis induced by cecal ligation and perforation (CLP) at different times and its relationship to nitric oxide synthases (NOS).Design and setting Prospective controlled trial in a university research laboratory.Subjects 102 male Sprague-Dawley rats.Interventions Groups 1–3 received sham laparotomy 6 h before lung isolation: group 1, only laparotomy; group 2, concurrently l-N ⁶-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg); group 3, concurrently N -nitro-l-arginine methylester (L-NAME, 5 mg/kg). Groups 4–6 received CLP 6 h before lung isolation: group 4, only CLP; group 5, concurrently L-NIL; group 6, concurrently L-NAME. The same experiments were carried out with sham and CLP treatment for 24 h (groups 7–12). Exhaled NO from rats lungs was measured after anesthesia and tracheostomy. After the pulmonary circuit was isolated and perfused, angiotensin II (0.1 µg) was injected into the inflow tract. The lungs were ventilated with the hypoxic mixture (HPV, 3% O₂) for 10 min and then again with the normoxic mixture (21% O₂) for an equal period. Changes in perfusion pressure were measured. Endothelial (eNOS) and inducible NOS (iNOS) expression of the lungs was determined.Measurements and results Treatment with L-NAME but not L-NIL increased HPV in sham lungs. HPV was unaltered after CLP 6 h and decreased after CLP 24 h compared to sham. In CLP animals eNOS protein expression was reduced whereas iNOS expression was increased compared to sham animals. Exhaled NO, reflecting NOS activity was twice as high in the CLP 24 h group than in the CLP 6 h group.Conclusions In the CLP sepsis model modulation of HPV was time-dependent. In addition, vasoconstriction to hypoxic stimuli was dependent on NOS activity.L.G. F. is supported by Innovative Medizinische Forschung Münster, Germany (Fi-1-2000-4)     

World health system performance revisited: the impact of varying the relative importance of health system goals

Background

In 2002, the World Health Organization published a health system performance ranking for 191 member countries. The ranking was based on five indicators, with fixed weights common to all countries.

Methods

We investigate the feasibility and desirability of using mathematical programming techniques that allow weights to vary across countries to reflect their varying circumstances and objectives.

Results

By global distributional measures, scores and ranks are found to be not very sensitive to changes in weights, although differences can be large for individual countries.

Conclusions

Building the flexibility of variable weights into calculation of the performance index is a useful way to respond to the debates and criticisms appearing since publication of the ranking.     

Development of an in vitro blood-brain barrier model based on immortalized porcine brain microvascular endothelial cells

Immortalized porcine brain microvessel endothelial cells (PBMEC/C1-2) were used to develop a model for measurement of blood-brain barrier permeation of central nervous system active drugs. Previous studies showed that a system using C6 astrocyte glioma conditioned medium leads to cell layers with transendothelial electrical resistance values up to 300 Omega cm(2) and a permeability coefficient P(e) of 3.24 +/- 0.14 x 10(-4) cm/min for U-[(14)C]sucrose, which is in good agreement to published values and thus indicates the formation of tight junctions in vitro. However, commercially available inserts for the Transwell system were not permeable for highly lipophilic compounds, such as diazepam. Systematic studies with different insert showed, that inserts with a pore width of 1 microm proved to be optimal for permeation studies of lipophilic compounds. Permeability studies with a set of three benzodiazepines further supported this finding.     

Usefulness of plasma brain natriuretic peptide levels in predicting dobutamine-induced myocardial ischemia

Plasma brain natriuretic peptide (BNP) levels have been associated with left ventricular dysfunction and acute myocardial infarction. Although natriuretic peptide responses have been linked to exercise-induced myocardial ischemia, it is not known whether BNP levels predict dobutamine-induced myocardial ischemia. The aim of this study was to determine whether elevations in BNP levels immediately before or after dobutamine-induced stress are associated with echocardiographic myocardial ischemia. Plasma BNP was measured before and after stress during dobutamine-stress echocardiography in 317 patients (aged 68 +/- 11 years; 46% women) who had creatinine <1.5 mg/dl and did not have valvular disease. Ischemia, as assessed by blinded echocardiographic interpretation, was noted in 31 patients (10%). In univariable analyses, prestress BNP was predictive of echocardiographic ischemia (rates of ischemia according to tertiles of BNP 4%, 9%, and 16%, chi-square for trend = 8, p = 0.0059). The change in BNP levels with dobutamine stress was not associated with ischemia. In multivariable analyses, after adjusting for age, gender, and left ventricular ejection fraction, BNP before and after stress remained predictive of ischemia (1 SD increase in the log of resting BNP adjusted odds ratio 2.0, 95% confidence interval 1.3 to 3.0, p = 0.002). In this pilot study, resting BNP was predictive of dobutamine-induced ischemia. Future work is needed to confirm these findings.     

Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration

INTRODUCTION: A thrombin inhibitor management (TIM) point-of-care test based upon the ecarin clotting time (ECT) has been developed. The ECT has been suggested to more accurately reflect the anti-coagulant effect of direct thrombin inhibitors compared with the activated clotting time (ACT). We sought to examine the correlation of the TIM-ECT test with bivalirudin concentration in patients undergoing percutaneous coronary intervention (PCI), and to compare the performance of this test with the current standard (i.e., ACT). MATERIALS AND METHODS: In a multicenter study, blood samples were obtained at six pre-defined time-points in 170 consecutive patients undergoing PCI using bivalirudin. For each sample, the TIM-ECT (citrated and non-citrated), ACT, and bivalirudin concentration was determined. RESULTS: Considering samples from all time-points (n=784), the correlations of TIM-ECT citrated, TIM-ECT non-citrated, and ACT with bivalirudin concentration were 0.96, 0.93, and 0.90, respectively. For samples collected at therapeutic levels of bivalirudin (n=353), the correlations of TIM-ECT citrated, TIM-ECT non-citrated, and ACT with bivalirudin concentration were lower, and showed a greater disparity between methods, with correlation coefficients of 0.75, 0.59, and 0.37, respectively. Prediction models based on the measured bivalirudin concentration were developed for TIM-ECT and ACT, and the coefficients of determination (r(2)) of actual versus predicted TIM-ECT and ACT were 0.91 and 0.81, respectively. CONCLUSIONS: In this PCI population, the TIM-ECT point-of-care test and ACT demonstrated a strong correlation with bivalirudin concentration. The TIM-ECT test had a higher correlation with bivalirudin concentration at therapeutic levels of the drug, and for individual samples appears to more consistently reflect the bivalirudin concentration compared with the ACT.     

The Munich vulnerability study on affective disorders: premorbid psychometric profile of affected individuals

OBJECTIVE: We conducted a longitudinal high-risk study to identify psychometric vulnerability markers for affective disorders. METHOD: We examined 82 healthy subjects [high-risk probands (HRPs)] with at least one first-degree relative suffering from an affective disorder. The premorbid psychometric profile of 20 HRPs who developed a psychiatric disorder during follow-up was compared with the profile of control subjects without personal and family history of psychiatric disorders matched for age and gender. RESULTS: Somatization, complaints (vegetative lability), and perception of strain are increased in HRPs who developed a psychiatric disorder. These alterations were not influenced by the time interval until the onset of the disorder. CONCLUSION: The premorbid psychometric profile in subjects at high risk for affective disorders is characterized by somatization, complaints, and elevated perception of strain. Together with previous findings our results suggest that these alterations can be regarded as potential vulnerability markers for affective disorders.