Structural modification of receptor-binding technetium-99m complexes in order to improve brain uptake

Low brain uptake is a generally accepted problem in developing technetium-99m brain receptor imaging agents. For a class of potential 5-HT_2A receptorbinding agents we tried to improve the original low brain uptake of 0.4% injected dose (ID) in rats 5 min p.i. by modifying the lipophilic properties of the molecules. Because of the presence of a protonable nitrogen, which according to the pK _a value leads to ionization of the molecule at blood pH, the pK _a value was considered to be the parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of five candidates lowers the apparent pK _a value from 10.0 to 8.3 and dramatically increases the brain uptake to 1.3% ID at 5 min. The direct relationship between brain uptake and apparent pK _a cannot be simply explained by the increase in the pK _a-governed proportion of the neutral species.     

Synthetic Colloids Attenuate Leukocyte-Endothelial Interactions by Inhibition of Integrin Function

Background: It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions.

Methods: Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm2. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils.

Results: Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31-51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins.     

Somatoform pain disorder in the general population

BACKGROUND: Chronic pain disorder is assumed to represent a frequent and disabling condition. However, data on the prevalence of somatoform pain symptoms and somatoform pain disorder in the community are limited to date. METHODS: German versions of the Composite International Diagnostic Interview were administered to a representative national sample of 4,075 people. Somatoform pain disorder was diagnosed by standardized diagnostic algorithm based on the DSM-III-R criteria (absence of adequate physical findings). One subgroup was identified as also meeting the DSM-IV criterion B for 'significant distress or psychosocial impairment due to the somatoform pain'. RESULTS: A lifetime prevalence rate of somatoform pain disorder according to DSM-III-R of 33.7% and a 6-month rate of 17.3% was found. When applying the DSM-IV B criterion, the prevalence rate dropped to 12.3 and 5.4%, respectively. In both groups more than 95% of the probands had contacted their doctor because of the pain. In 25% of the probands the pain was positively assigned to psychological factors. A female:male ratio of 2:1 was found. CONCLUSIONS: Somatoform pain disorder (DSM-III-R) is a frequent condition. However, only about one third of these subjects is severely distressed or impaired by the pain. A clear operationalized concept of the DSM-IV criterion C 'psychological factors are judged to have an important role in the onset, severity, exacerbation or maintenance of the pain' should be provided in the further development of the diagnosis 'pain disorder' in order to make this diagnosis suitable for general population surveys.     

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

ABSTRACT: BACKGROUND: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcome and may bias patient selection. DISCUSSION: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of the assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrolment fraction with regard to its representativeness of the eligible population. SUMMARY: We propose a list of measures to be taken to improve the external validity of double-blind, placebo-controlled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself.     

Covered self-expanding stent treatment for anastomotic leakage: outcomes in esophagogastric and esophagojejunal anastomoses

Background

Anastomotic leakage of esophagogastric and esophagojejunal anastomoses is a severe complication after esophagectomy and gastrectomy associated with a high mortality. We conducted this non-randomized observational study to evaluate the outcomes and clinical effectiveness of covered self-expanding stents (CSESs) in treating esophageal anastomotic leakage.

Methods

From 2002 to 2013, consecutive patients with anastomotic leakage after esophagogastrostomy or esophagojejunostomy who received CSESs were analyzed concerning leakage characteristics, leakage sealing rate, success and failure rates of CSES treatment, stent-related complications, and mortality.

Results

In 35 patients, anastomotic leakage originating from 5 cervical esophagogastrostomies, 6 thoracic esophagogastrostomies, 12 mediastinal esophagojejunostomies and 12 abdominal esophagojejunostomies were treated with 48 CSESs (16 fully CSES, 32 partially CSES). Of 35 patients, 24 received one stent, 9 received two consecutive stents, and 2 received three consecutive stents. Stent-related complications occurred in 71 % of patients (25/35). The most frequent complications were leakage persistence (44 %) and stent dislocation (19 %). Sealing of the anastomotic leakage was achieved in 24 (69 %) patients after a median (range) stenting time of 19 (1–78) days. Sealing rates differed significantly with 20 % (cervical esophagogastrostomies), 50 % (thoracic esophagogastrostomies), 92 % (mediastinal esophagojejunostomies) and 67 % (abdominal esophagojejunostomies) of patients (p = 0.023). Moreover, clinical success rates differed among these groups (60 vs. 67 vs. 92 vs. 58 %; p = 0.247). Clinical failure of stent treatment was more likely to be recognized in early postoperative leakage (median postoperative day 3 vs. 8; p = 0.098) compared with successful treatment, whereas no difference for clinical success rates was found comparing leakage ≤10 versus >10 mm (68 vs. 64 %; p = 0.479).

Conclusion

CSESs are an effective treatment for anastomotic leakage in patients with esophagogastrostomies and esophagojejunostomies. Best results can be achieved in patients with anastomotic leakages following mediastinal esophagojejunostomy, and in leakages occurring after the very early postoperative phase.     

Correlation of hippocampal glucose oxidation capacity and interictal FDG-PET in temporal lobe epilepsy

PURPOSE: Interictal [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) demonstrates temporal hypometabolism in the epileptogenic zone of 60-90% of patients with temporal lobe epilepsy. The pathophysiology of this finding is still unknown. Several studies failed to show a correlation between hippocampal FDG-PET hypometabolism and neuronal cell loss. Because FDG is metabolized by hexokinase bound to the outer mitochondrial membrane, we correlated the glucose-oxidation capacity of hippocampal subfields obtained after surgical resection with the corresponding hippocampal presurgical FDG-PET activity. METHODS: In 16 patients with electrophysiologically confirmed temporal lobe epilepsy, we used high-resolution respirometry to determine the basal and maximal glucose-oxidation rates in 400-microm-thick hippocampal subfields obtained after dissection of human hippocampal slices into the CA1 and CA3 pyramidal subfields and the dentate gyrus. RESULTS: We observed a correlation of the FDG-PET activity with the maximal glucose-oxidation rate of the CA3 pyramidal subfields (rp = 0.7, p = 0.003) but not for the regions CA1 and dentate gyrus. In accordance with previous studies, no correlation of the FDG-PET to the neuronal cell density of CA1, CA3, and dentate gyrus was found. CONCLUSIONS: The interictal hippocampal FDG-PET hypometabolism in patients with temporal lobe epilepsy is correlated to the glucose-oxidation capacity of the CA3 hippocampal subfield as result of impaired oxidative metabolism.