[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.

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.

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.

[Diagnosis of Hermansky-Pudlak syndrome]. / Diagnostik des Hermansky-Pudlak-Syndroms.

HISTORY AND ADMISSION FINDINGS: A 27-year-old woman presented with increased bleeding tendency and known oculocutaneous albinism. In addition to frequent nasal and gingival bleedings she had since childhood spontaneous extensive cutaneous bleedings. In addition she was extreme sensitive to UV light with visual disturbances. Bone-marrow biopsy when aged 9 years had revealed abnormal pigment-storing cells. Physical examination showed a very fair skin and hair, spontaneous nystagmus and extensive rash in the face. INVESTIGATIONS: Prothrombin, partial thromboplastin and thrombin times as well as fibrinogen level were normal. On re- admission bleeding time varied greatly, while platelet count was normal. Mean platelet volume was slightly reduced. Von Willebrand antigen, factor VIII:C, factor IX:C, factor XIII and alpha (2)-antiplasmin were all normal. Aggregometry indicated abnormal platelet function; there was reduced platelet aggregation after stimulation with adenosine diphosphate. Flow cytometry of whole blood demonstrated abnormal storage function of thrombocytic delta-granules. The underlying cause of the described symptoms was shown to be a gene defect in typical location on the long arm of chromosome 10. DIAGNOSIS AND TREATMENT: The triad of tyrosinase-positive oculocutaneous albinism, abnormal thrombocytic delta-granules and ceroid deposition in the cells of the reticuloendothelial system or the bone-marrow is called Hermansky-Pudlak syndrome (after those who first reported it). There is as yet no causal treatment. But the patient was advised to use a nasal spray of desmopressin for spontaneous or difficult to stop bleedings after minor injuries. Desmopressin i. v. should be given prophylactically before any operation.

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.

[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.

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.

[Grönblad-Strandberg syndrome from the angiological viewpoint]. / Das Grönblad-Strandberg-Syndrom aus angiologischer Sicht.

HISTORY AND CLINICAL FINDINGS: A 42-year-old man was admitted for treatment of peripheral vascular disease in the left leg (stage III of Fontaine). A year before he had undergone a right aortofemoral bypass operation. On admission there was stenosis of the left pelvic axis and bilateral femoral artery occlusion. In addition there were changes in the skin with abnormal folds, loss of elasticity and yellowish spots over the sides of the neck and the flexor surfaces of all large joints. In addition vision in the left eye was impaired. These findings suggested connective tissue disease involving the skin, eye and arterial system. INVESTIGATIONS: Routine haematological tests were normal as were clotting parameters. Serum concentration of GOT, GPT, gamma-GT were slightly increased. There was a dysproteinaemia with raised HDL and LDL levels. Resting electrocardiogram was normal, showing sinus rhythm and left axis deviation. The crurobrachial pressure index was clearly abnormal: 0.6 on the right and 0.5 on the left. Angiography of the pelvic and left arteries revealed long-segment femoral and partial lower-leg occlusions bilaterally. Abdominal sonography indicated diffuse parenchymal calcifications in both kidneys and angioid streaks on bilateral fundoscopy. Skin biopsy showed defects of elastic fibres and perivascular inflammatory infiltration, while capillary microscopy revealed twisting of the capillaries, most of them with normal lumen. These findings taken together indicated pseudoxanthoma elasticum (PXE) or Grönblad-Strandberg syndrome. TREATMENT AND COURSE: A thrombendarterectomy was performed on the left superficial femoral artery, after which the left popliteal artery became palpable, the pressure indices for the left leg were slightly better, and the patient was discharged home without further complications and improved leg perfusion. CONCLUSION: Possible cardiovascular involvement had to be taken into account in patients with PXE, and long-term angiological monitoring is indicated.

[The aortic arch as the source of a peripheral arterial embolism]. / Der Aortenbogen als Quelle einer peripheren arteriellen Embolie.

HISTORY AND CLINICAL FINDINGS: On the day before admission a 68-year-old woman had an acute episode of incomplete ischaemia of the left lower arm. She had no known heart disease and her general condition was unchanged. There were no palpable pulses in the cold and pale lower arm. Sensory and motor functions of the left hand were slightly impaired. Arterial embolisation was suspected. INVESTIGATIONS: The blood picture was normal, erythrocyte sedimentation rate 20/50 mm, C-reactive protein elevated to 7.0 mg/l. There was no evidence of clotting abnormality. The resting ECG showed normal sinus rhythm. Doppler ultrasound gave a systolic pressure of 80 mm Hg over the radial artery and 50 mm Hg over the ulnar artery, with a systemic systolic pressure of 140 mm Hg. No intracardiac thrombi were seen on echocardiography. Transoesophageal echocardiography revealed a 2 x 3 cm hypermobile mass in the distal aortic arch, most likely a thrombus as the source of the embolus. Contrast computed tomography and digital subtraction angiography also demonstrated the mass. TREATMENT AND COURSE: At first heparin (bolus of 5000 IU, then 1000 IU/h) was infused. One day after the diagnosis had been established thrombectomy of the aortic arch and embolectomy of the left brachial artery were performed without complication. The patient was discharged on the 15th post-operative day on a maintenance dose of phenprocoumon. Histological examination of the surgical specimen from the aorta showed a separating thrombus on an ulcerating atherosclerotic plaque. CONCLUSION: The importance of the thoracic aorta as a source of emboli is often underestimated. Transoesophageal echocardiography is a reliable method to demonstrate aortic thrombi.

Comparison of Laparoscopic versus Conventional Treatment of Ovarian Endometrioma

An observational prospective cohort study was conducted with a historical control group and 140 infertile women with the laparoscopic diagnosis of ovarian endometrioma over 1 cm diameter. The groups were comparable regarding age, duration of infertility, and disease severity. All patients had a follow-up of 12 months after treatment, and at least one patent tube. The laparoscopic group (group A) consisted of 46 woman, 35 of whom received suppressive treatment with danazol, Gestinone, or leuprolide acetate for 4 to 6 months. In the control group (group B), 94 women underwent diagnostic laparoscopy plus 6 months of danazol or Gestinone therapy. After 3 months, microsurgery by laparotomy was performed. During the follow-up, period 24 pregnancies were achieved in group A (52%) and 58 in group B (61%, chi2 0.796). Fifteen (48%) of 31 women with cysts 1 to 3 cm in group A conceived, as did 52 (62%) of 81 in group B. Nine (60%) of the 15 with cysts over 3 cm in group A, and 7 (58%) of 12 in group B conceived. No significant difference was found among the suppressive drugs in either group. Only 4 (36%) of the 11 women in group A not receiving suppressive treatment became pregnant. No significant difference (p >0.05) was found when comparing the combined treatment group (57%). According to the revised classification of endometriosis, 18 (51%) of 35 pregnancies were achieved in women with moderate disease in group A and 41 (64%) of 64 in group B. In those with severe disease, 6 (55%) of 11 became pregnant in group A and 17 (57%) of 30 in group B. There was no significant difference between the groups when comparing global results, ovarian endometrioma size, medical treatment, and severity of endometriosis. Given comparable surgical expertise, operative laparoscopy should be the procedure of choice in the treatment of ovarian endometrioma whenever possible, due to its recognized advantages.

[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.