A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.

Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.

[18F]-florbetaben PET/CT Imaging in the Alzheimer's Disease Mouse Model APPswe/PS1dE9.

BACKGROUND: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aß), a pathological hallmark of Alzheimer's disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aß plaques. METHODS: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aß plaque load in cortex, hippocampus and cerebellum were analyzed. RESULTS: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. CONCLUSION: The findings suggest that histopathological characteristics of Aß plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

Impact of the Reticular Stress and Unfolded Protein Response on the inflammatory response in endometrial stromal cells.

During decidualization, endometrial stromal cells undergo reticular stress (RS) and unfolded protein response (UPR), allowing the endoplasmic reticulum-expansion and immunomodulators production. Physiological RS generates the activation of sensing proteins, inflammasome activation and mature-IL-1ß secretion, associated with pro-implantatory effects. We focus on the impact of RS and UPR on decidualized cells and whether they induce a physiological sterile inflammatory response through IL-1ß production. Human endometrial stromal cell line (HESC) after decidualization treatment with MPA + dibutyryl-cAMP (Dec) increased the expression of RS-sensors (ATF6, PERK and IRE1α) and UPR markers (sXBP1 and CHOP) in comparison with Non-dec cells. Then we found increased NLRP3 expression in Dec cells compared with Non-dec cells. In fact STF-083010 (an IRE1α inhibitor) prevented this increase. Downstream, increased levels of active caspase-1 on Dec cells were detected by FAM-Flica Caspase-1 associated with an increase in IL-1ß production. Moreover, the treatment with STF-083010 decreased the invasion index observed in Dec cells, evaluated by an in vitro model of implantation. In endometrial biopsies from recurrent spontaneous abortion patients an increased expression of IRE1α was found in comparison with fertile women; while recurrent implantation failure samples showed a lower expression of sXBP1, TXNIP and NLRP3 than fertile women, suggesting that RS/UPR tenors might condition endometrial receptivity.

Isolation of the oncogene and epidermal growth factor-induced transin gene: complex control in rat fibroblasts.

Various oncogenes or epidermal growth factor (EGF) induce transcription of a 1.9-kilobase RNA (transin RNA) in rat fibroblasts. The induction by EGF can be blocked by cycloheximide. Thus the response of the transin gene to EGF appears to require de novo protein synthesis. Transin RNA induction is specific to EGF, as neither insulin, platelet-derived growth factor, fibroblast growth factor, nor transforming growth factor beta could elicit the same response. However, transforming growth factor beta could block the EGF induction of transin RNA. Whereas the calcium ionophore A23187 and the tumor promoter TPA, either alone or administered together, did not increase transin RNA levels, TPA could synergise with a serum factor to effect such an increase. Dibutyryl cyclic AMP also induced transin RNA. Treatment of cells with the microfilament-disrupting agent cytochalasin B, but not the microtubule-disrupting agent colcemid, resulted in an increase in transin RNA levels, suggesting a role for the cytoskeleton in control of transin gene expression. The transin RNA does not contain repeated sequences and appears to be encoded by a single-copy gene. The protein sequence encoded by the last four exons of the transin gene shows some homology to two regions of the heme-binding protein hemopexin.

Layersome: development and optimization of stable liposomes as drug delivery system.

This paper describes the development of stable drug delivery systems named layersomes. The layersomes are conventional liposomes coated with one or multiple layers of biocompatible polyelectrolytes in order to stabilise their structure. The formulation strategy is based on an alternative coating procedure of positive poly(lysine) (pLL) and negative poly(glutamic acid) (pGA) polypeptides on initially charged small unilamellar liposomes (SUVs). The size distribution and the zeta potential of the final entity depend on the number of polyelectrolyte layers and the charge of the last coating layer. Morphological studies were achieved by flux cytometry and cryo electron microscopy. Release studies of encapsulated hydrophilic 5(6)-carboxyfluorescein (5,6CF) in the presence of Triton or ethanol showed an increased membrane resistance of the layersomes compared to classical SUVs. Finally, encapsulation of piroxicam (PX) was performed with success.

Interaction between dextran and human low density lipoproteins (LDL) observed using laser light scattering.

Dextran infusions in humans lead to a reduction of low density lipoproteins (LDL) in the plasma compartment. The interaction of dextran with human LDL was investigated in vitro by static and dynamic light scattering. The experiments were performed with human LDL (apoB concentration 0.75 g l(-1)) and dextran (Mw = 40,000 and 70,000 g mol(-1)) at 25 degrees C. The dextran concentrations after mixing were 10 and 50 g l(-1). The hydrodynamic radius for native LDL was found to be RH = 12.9 nm. The addition of dextran induces the formation of LDL associates with a mean radius of RH approximately 200 nm. These findings show that even non-sulphated polysaccharides interact with LDL. The dextran-dependent formation of LDL associates detected in vitro could be the reason for the in vivo effect of dextran on the lipid metabolism.

Serological evidence of Chlamydia pneumoniae lipopolysaccharide antibodies in atherosclerosis of various vascular regions.

BACKGROUND: The role of Chlamydia pneumoniae in the pathogenesis of atherosclerosis has so far mainly been investigated in patients suffering from coronary heart disease; the other vascular regions have virtually been ignored. The aim of this study was to carry out a statistical survey of serological markers of a C. pneumoniae infection in patients with different patterns of atherosclerosis manifestation. PATIENTS AND METHODS: 340 patients were examined for the atherosclerotic alteration of peripheral arteries of the lower limbs, carotid arteries and coronary arteries by ultrasound scan and/or angiography. Immunoglobulin(Ig)G and IgA-rELISA were used to measure chlamydial lipopolysaccharide antibodies. Species determination was performed using the IgG micro-immunofluorescence test. RESULTS: 24.0% of atherosclerotic cases (A) and 52.3% of controls (C) were negative for C. pneumoniae lipopolysaccharide antibodies (p = 0.00002). By contrast, 45.1% of atherosclerotic cases and 16.9% of controls were positive for both IgG and IgA (p = 0.00002). The mean antibody titers of the atherosclerosis group were higher than in the control group (IgG positive xAIgG = 344, xCIgG = 272; IgG and IgA positive xAIgG = 576, xCIgG = 486 and xAIgA = 120, xCIgA = 91). Concerning atherosclerosis manifestation in various vascular regions, no significant differences were found between IgG and IgA antibody titers and prevalence. CONCLUSIONS: The results show that a persistent C, pneumoniae infection with evidence of lipopolysaccharide immunoglobulin G and A is equally associated with the atherosclerotic alteration of coronary arteries, carotid arteries and peripheral arterial occlusive disease, irrespective of the severity of atherosclerosis and with no predisposition to any particular vascular region.

[Recurrent coumarin necrosis in type II protein S deficiency]. / Rezidivierende Cumarinnekrose bei Protein S-Mangel vom Typ II.

Coumarin necrosis is a rare but clinical very important complication of therapy with coumarin derivatives. We report a patient with congenital protein S deficiency type II, who developed coumarin necrosis during stabilization of phenprocoumon. Diagnostic problems and therapeutic alternatives are discussed considering the recent literature.

[Radioimmunologic determination of serum testosterone concentration in healthy male probands]. / Radioimmunologische Bestimmung der Testosteronserumkonzentration bei gesunden männlichen Probanden.

By means of the test set Testosterone-RIA SSW age-depending areas within the normal of the total hormone level of testosterone in the serum was established in 122 healthy male test persons. The examination resulted in an increase of the testosterone concentration from the 20th to the 55th year of age and a following exponential decrease. The exactness of the intraassay lies in the mean region of concentration at 8-12% and the exactness of the interassay between 10-20%. The sensitivity of the determination is 2.7 +/- 1.8 nmol testosterone/l.

Transcriptionally active SV40 minichromosomes are restriction enzyme sensitive and contain a nucleosome-free origin region.

A nucleosome-free region or gap containing the origin of replication and the transcriptional promoter elements is observed on 20 to 25% of the SV40 minichromosomes isolated at physiological ionic strength late in infection. We used the preferential sensitivity of the gapped minichromosomes to restriction enzymes to obtain sucrose gradient fractions containing 50 to 80% of gapped molecules. The same fractions are also enriched in RNA polymerase B (II) molecules engaged in transcription. Using electron microscopy, we demonstrate here that the transcriptional complexes are preferentially sensitive to restriction enzyme digestion, which indicate that they represent a subpopulation of the gapped minichromosomes.

[Effect of low and high molecular weight dextrans on selected serum lipid parameters. 1]. / Der Einfluss nieder- und höhermolekularer Dextrane auf ausgewählte Lipidparameter im Serum. 1. Mitteilung.

Three male patients with hyperlipidaemia were given daily infusions of dextran over a period of 10 days. Plasma levels of total cholesterol, LDL and HDL cholesterol, apolipoprotein B and AI and triglycerides were analysed after the infusion of dextrans different in dose and molecular size. Dextrans caused alterations of some plasma lipids and lipoproteins exceeding the haemodilution effect. The degree of lipid lowering depends on the volume and molecular size of the administered dextran.

[Aneurysm of the ascending aorta in tertiary syphilis]. / Aneurysma der Aorta ascendens bei tertiärer Lues.

HISTORY AND CLINICAL FINDINGS: A 58-year-old man was admitted after he was found to have a huge aneurysm of the thoracic aorta. 38 months previously he had first experienced subacute pain in the right thorax. After this the aneurysm gradually increased in size. On admission a pulsating mass, 20 cm in diameter, was obvious, having broken through the right ventral thoracic wall. It was causing venous inflow congestion in the upper part of the body. The patient's general condition was poor: he had marked orthopnoea. INVESTIGATIONS: Serological tests for syphilis gave the following results: VDRL test, 1:32; FTA-ABS test reactive; TPHA test, 1:8000; treponema-specific IgM negative. Computed tomography with contrast-medium injection exactly defined site and extent of the aneurysm. It started at the aortic root and extended to the aortic arch. Third-degree aortic valvar regurgitation was demonstrated on echocardiography. Pulmonary function tests indicated severe restrictive ventilatory abnormality with clearly reduced respiratory reserve. TREATMENT AND COURSE: The symptoms improved after 2 weeks on oral medication of captopril (25 mg/d), furosemide (80 mg/d), spironolactone (100 mg/d), codeine phosphate (90 mg/d) and thick paraffin (20 mg/d as needed). The patient declined further treatment. He died 8 weeks later at home.

[Acute abdomen in extensive thrombosis in the inferior vena cava collateral circulation]. / Akutes Abdomen bei ausgedehnter Thrombosierung im Stromgebiet der Vena cava inferior.

Variations of the inferior vena cava (IVC) because of either embryonal malformations or postthrombotic changes are not uncommon. The clinical symptoms include repetitive thrombotic events. We report on an atypical case of acute abdomen resulting from thrombotic occlusion of the IVC and the right renal vein as well as of the collateral vessels.

[The effect of low and high molecular weight dextrans on selected lipid parameters in serum. Part 3]. / Der Einfluss nieder- und höhermolekularer Dextrane auf ausgewählte Lipidparameter im Serum. 3. Mitteilung.

After a ten-day treatment of 21 patients with low molecular weight dextran (MW = 40,000), a decrease in the plasma concentrations of total cholesterol of 25%, LDL-cholesterol of 32% and apoprotein B of 22% was observed. The HDL fraction only showed a reduction of 10%. These dextran effects were dose-dependent. During the post-treatment period of 20 days a continuous increase in the lipid parameters to the preinfusion values was demonstrated. Dextran caused stronger lipid changes in HLP patients than in normolipaemics.

[Alcohol-induced toxic hepatitis--a "free radical" associated disease. Lowering fatality by adjuvant antioxidant therapy]. / Alkoholtoxische Hepatitis--eine "freie Radikale"-assoziierte Erkrankung. Letalitätssenkung durch adjuvante Antioxidantientherapie.

Toxic liver diseases coincide with oxidative stress correlating positively with the seriousness of the course of disease. For the purpose of elucidating the pathogenic significance of an increased radical generation. 56 patients suffering from acute alcohol-toxic hepatitis of the clinical grade of seriousness B and C according to Child/Pugh were classified randomly into antioxidant subgroups (n = 31) and control groups (= 25). The basis therapy being identical, the patients of the antioxidant group received additionally 600 mg of D-alpha tocopherol per day, 200 micrograms of selenium and 12 mg of zinc. Due to the supplementation of antioxidants there were quicker significant changes in the concentration of bilirubin, malondialdehyde and of ammonia in the serum. In comparison with the control group the length of stay in hospital could be reduced by 6 days. In the control group the mortality rates amounted to 40% (10 of 25), in the antioxidant group to 6.5% (2 of 31). The results confirm the pathogenic significance of oxidative stress in alcohol-toxic liver disease because a distinct improvement of prognosis could be achieved by using a low-cost adjuvant antioxidant supplementation.

[Diabetes mellitus--a free radical-associated disease. Results of adjuvant antioxidant supplementation]. / Diabetes mellitus--eine mit Freien Radikalen assoziierte Erkrankung. Resultate einer adjuvanten Antioxidantiensupplementation.

Our investigations carried out in patients with diabetes mellitus revealed oxidative stress loads. The study presented here was to clarify whether a therapy with antioxidants can contribute to an improvement of prognosis. 80 patients affected with a long term diabetic late syndrome were randomised and arranged to 4 groups of n = 20 each. In contrast to a control group these patients received 600 mg of alpha lipoic acid or 100 micrograms of selenium (sodium selenite) daily or 1200 IE of D-alpha-tocopherol respectively for a time of 3 months. In comparison with the control group all groups treated in an antioxidative way showed significantly diminished serum concentrations of thiobarbituric acid reactive substances and of urinary albumin excretion rates. The symptoms of distal symmetric neuropathy measured according to the thermo- and vibration sensitivity also improved in a highly significant manner. The results prove that oxidative stress plays a promoting role in developing of long term diabetic late complications and that a therapy with adjuvant antioxidants may lead to a regression of diabetic late complications.

[In vitro effects of low molecular weight dextran on the surface properties of LDL]. / In-vitro-Effekte von niedermolekularem Dextran auf die Oberflächeneigenschaften von LDL.

The relative number of free amino groups on the surface of low density lipoproteins (LDL) was determined after the incubation with low molecular weight dextran (MW 40,000) in several concentrations by two different assays (fluorescamine, TNBS). A decrease of the detectable free amino groups of 40% was shown by both assays. After the incubation of lysine with dextran these changes could not be observed. These results are explained with the aggregation of LDL particles influenced by dextran.