Dynamische kontrastverstärkte MRT zur Beurteilung der Knochenmarksmikrozirkulation bei malignen hämatologischen Erkrankungen vor und während einer Thalidomidtherapie

Purpose. The aim of the study was to measure microcirculation parameters by dynamic contrast-enhanced MRI (d-MRI) and to evaluate the anti-angiogentic effects during treatment with thalidomide in different hematologic malignancies. Methods. In 20 healthy normal persons, 20 patients with myelodysplastic syndromes (MDS), 10 patients with multiple myeloma (MM) and 10 with myelofibrosis (MF) a fast gradient echo sequence (Turbo fast low angle shot 2D) with a pump controlled bolus infusion of gadolinium-DTPA was performed before and in 18 of these after beginning (average of 4,3 months) of a thalidomide therapy. Two pharmacokinetic parameters – the amplitude and exchange-rate-constant – were calculated and a statistical comparison of these values between healthy persons and patients as well as a correlation with the clinical course was executed. Results. Compared with the normal controls the patients showed a higher amplitude (normal persons 14.4±5.2, MDS 24.8±8.1, MF 35.9±4.3, MM 23.4±3.6) and exchange-rate-constant (normal persons 0.124±0.042, MDS 0.136±0.036, MF 0.144±0.068, MM 0.131±0.034). In the d-MRI-follow-up examinations a significant (p<0.005) reduction of the amplitude and exchange rate constant values was evident in 14 of 18 patients undergoing a thalidomide therapy. Clinically all of these patients showed a therapy responding with complete or partial diseases remission. Conclusions. In patients with hematologic malignancies significantly higher d-MRI-microcirculation parameters of the lumbar spine can be demonstrated than in normal persons. During anti-angiogenetic treatment with thalidomide a decrease of these values was observed in case of a responding to therapy.     

Changes in inflammatory,coagulopathic, and fibrinolytic responses after endovascular repair of an abdominal aortic aneurysm: relationship between fibrinogen degradation product levels and endoleaks

Purpose

To compare the inflammatory, coagulopathic, and fibrinolytic responses after endovascular aneurysm repair (EVAR) of an abdominal aortic aneurysm between two stent grafts. Fibrinogen degradation product (FDP) levels were compared between patients with or without an endoleak.

Materials and methods

EVAR was performed in 88 patients using an Excluder (37 patients) or a Zenith (51 patients). White blood cell count (WBC), C-reactive protein (CRP) levels, platelet count, and FDP levels were measured before and after EVAR.

Results

WBC and CRP increased and the platelet count decreased significantly on days 1 and 3 after EVAR in the Zenith group compared with the Excluder group. The change in FDP from baseline to 7 days after EVAR was ?1.99 ± 7.46 vs. 8.59 ± 9.38 μg/mL in patients with (n = 24) vs. without (n = 64) an endoleak (p < 0.001). A change in FDP of 3.1 μg/mL was the optimal cutoff point for predicting the presence of an endoleak (accuracy 0.762; sensitivity 0.875; specificity 0.717).

Conclusion

Inflammatory, coagulopathic, and fibrinolytic responses were greater in the Zenith group than in the Excluder group. A change in FDP of ≤3.1 μg/mL was predictive of an endoleak after EVAR.     

Assessment of therapeutic response in ankylosing spondylitis patients undergoing anti-tumour necrosis factor therapy by whole-body magnetic resonance imaging

Objectives

Multifocal musculoskeletal inflammation is common in ankylosing spondylitis (AS) and is effectively treated by expensive anti-TNF (tumour necrosis factor) therapy. This study evaluated assessment of response by whole-body (WB) MRI compared with clinical assessment in AS patients during etanercept therapy.

Methods

Ten patients with AS underwent a 12-month therapy with etanercept. Clinical markers were monitored [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP)] and patients underwent WBMRI (1.5 T, STIR and T1-weighted) at three different time points (0, 26 and 52 weeks). WBMRI was evaluated and correlated with clinical scores.

Results

The BASDAI index decreased under therapy from 5.5?±?0.5 (week 0) to 1.7?±?0.5 (week 52, P?<?0.05). CRP declined from 15.7?±?2.2 mg/dl (week 0) to 0.9?±?0.9 mg/dl (week 52, P?<?0.05). In WBMRI, the sum of all lesions showed a significant decrease from week 0 (38.9?±?3.4) to week 52 (2.2?±?0.9, 94.3 % reduction). WBMRI detected more areas of synovitis and enthesitis than clinical examination alone.

Conclusions

AS activity significantly decreased under etanercept therapy, which was proven by clinical examination and WBMRI. WBMRI detected more inflammatory lesions than clinical examination alone. The results suggest that WBMRI improves the detection of inflammatory changes and the assessment of their course under therapy.

Key Points

? Multifocal musculoskeletal inflammation in AS is effectively treated by anti-TNF therapy. ? Inflammatory lesions can be assessed by clinical examination and whole-body MRI. ? AS activity significantly decreased under therapy as shown by WBMRI/clinical examination. ? WBMRI detected more inflammatory lesions than clinical examination alone. ? WBMRI improves detection of inflammatory changes and may help evaluation of therapy.     

Percutaneous cholecystostomy as the sole treatment in critically ill and elderly patients

Purpose

This study was done to investigate the effectiveness and clinical outcome of percutaneous cholecystostomy (PC) of treating acute cholecystitis in critical ill and elderly patients.

Materials and methods

In the last 3 years, PC was performed on 30 elderly and critically ill patients (17 men, 13 women; mean age 78.6, range 57?C97 years) with acute cholecystitis and comorbid diseases.

Results

Technical success was 30/30 (100%). Clinical effectiveness was 30/30 (100%), with statistically significant reductions in while blood cell (WBC) count, C-reactive protein (CRP) and fever. Mean WBC upon admission (19.87×10³±1.61×10³ /??l), axillary temperature (38.2±0.11 °C), and CRP (248.7±4.76 mg/l) values were significantly decreased in the 72 h following PC [12.9×10³ ± 1.05×10³/??l (p??0.0001), 37 ± 0.04 °C (p??0.0001), 113.5 ± 3 mg/l (p??0.0001), respectively]. Clinical and ultrasonographic (US) signs of acute cholecystitis decreased in all patients. There were no major complications or procedure-related deaths, and the morbidity rate was low (3/30; 10%).

Conclusions

PC appears to be a fast, easy and effective treatment for the acute phase of cholecystitis in elderly and critically ill patients. Procedure-related morbidity and mortality rates are very low compared with surgery. Conservative treatment for patients who are not eligible for surgery is acceptable.     

Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis

Background

Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked.

Methods

Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with ^99mTc-labeled matrix metalloproteinase inhibitor (MPI) and ¹¹¹In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes.

Results

MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 ± .018%) and AA5 (.03 ± .01%) uptake was higher in HC than control (n = 6) animals (.014 ± .004%, P < .0001; .0007 ± .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes.

Conclusions

The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.     

Chemical analysis of a benzofuran derivative, 2-(2-ethylaminopropyl)benzofuran (2-EAPB), eight synthetic cannabinoids,five cathinone derivatives,and five other designer drugs newly detected in illegal products

From November 2013 to May 2014, 19 newly distributed designer drugs were identified in 104 products in our ongoing survey of illegal products in Japan. The identified compounds included 8 synthetic cannabinoids, FUB-PB-22 (1), 5-fluoro-NNEI indazole analog (5-fluoro-MN-18, 2), AM-2201 indazole analog (THJ-2201, 3), XLR-12 (4), 5-fluoro-AB-PINACA (5), 5-chloro-AB-PINACA (6), AB-CHMINACA (7), and 5-fluoro-AMB (8); 5 cathinone derivatives, DL-4662 (9), α-PHP (10), 4-methoxy-α-POP (11), 4-methoxy-α-PHPP (12), and 4-fluoro-α-PHPP (13); and 6 other substances, namely, the benzofuran derivative 2-(2-ethylaminopropyl)benzofuran (2-EAPB, 14), nitracaine (15), diclofensine (16), diphenidine (17), 1-benzylpiperidine (18), and acetylfentanyl (19). To our knowledge, this is the first report on the chemical properties of compounds 9–11 and 14. A total of 33 designer drugs, including compounds 1–19, were detected in the 104 illegal products, in 60 different combination patterns. The numbers of detected compounds per product ranged from 1 to 7. In addition, several products contained three different types of compounds, such as synthetic cannabinoids, cathinone derivatives, and phenethylamine derivatives per product. It is apparent that the types of compounds emerging as illegal products are becoming more diverse, as are their combinations.     

Identification of two new-type designer drugs, piperazine derivative MT-45 (I-C6) and synthetic peptide Noopept (GVS-111), with synthetic cannabinoid A-834735, cathinone derivative 4-methoxy-α-PVP, and phenethylamine derivative 4-methylbuphedrine from illegal products

We identified two new-type designer drugs, piperazine derivative MT-45 [1-cyclohexyl-4-(1,2-diphenylethyl)piperazine, synonym: I-C6, 1] and synthetic peptide Noopept [ethyl 2-(1-(2-phenylacetyl)pyrrolidine-2-carboxamido)acetate, synonym: GVS-111, 2], in chemical and herbal products. MT-45 (1) was previously reported as an opiate-like analgesic substance, and Noopept (2) was reported to have nootropic (cognitive enhancer) activity. We also detected two synthetic cannabinoids, A-834735 (3) and QUPIC N-(5-fluoropentyl) analog (synonym: 5-fluoro-PB-22, 4), in the illegal products. A-834735 (3) was previously reported to act as an agonist at both cannabinoid CB₁ and CB₂ receptors. In addition, cathinone derivative 4-methoxy-α-pyrrolidinovalerophenone (4-methoxy-α-PVP, 5) and phenethylamine derivative 4-methylbuphedrine (6) were newly detected with known cathinone derivative 4-methylbuphedrone (7) in the products.     

C-reactive protein (CRP) in different types of minimally invasive knee arthroplasty

Purpose

C-reactive protein (CRP) is an acute-phase biomarker responding to surgical trauma. Typically, a first peak is observed at day 2 with a reduction at day 4 and normalization 3–6 weeks after surgery. CRP is often linked to prosthetic joint infection when elevated values are present longer time after surgery. The aim of this study was to analyse the kinetics of CRP in different types of minimally invasive (MI) arthroplasty and to observe if there were significant differences in between MI total knee arthroplasty (TKA), patient-specific instruments (PSI) TKA and unicompartmental arthroplasty (UKA).

Materials and methods

Three hundred and seventy-two patients were prospectively studied with a blood test measuring CRP at day 2, 4, 21 and 42 in 3 different groups of patients: 257 MI TKA, 55 PSI TKA and 60 UKA. Mean peak values and kinetics were compared in between different groups of MI arthroplasty.

Results

There was a significant age difference in the three MI arthroplasty groups. The difference in mean age for the conventional MI TKA group of 68.8 ± 9.8 years, 58.5 ± 11.7 years for the unicompartmental group (P < 0.05) and 63.3 ± 9.6 years for the PSI group (P < 0.05) was significant. Mean CRP level, for the entire study group, on day 2 was 16.7 ± 8.8 mg/dl that gradually decreased to 13.6 ± 7.8 mg/dl on day 4. On day 21 and 42, median CRP level was 0.6 (0–20) and 0.4 (0–7) mg/dl, respectively. Peak CRP values were lower for UKA compared to TKA at day 2 (11.6 vs. 17.5 mg/dl) and day 4 (8.0 vs. 15 mg/dl), but this was not observed for PSI–assisted arthroplasty (18.9 vs. 17.5 mg/dl). There was a trend for faster CRP normalization in UKA compared to the two other groups at day 21 and at day 42 and for PSI TKA to have a lower mean level at 4 days (12.9 vs. 15 mg/dl). There was no statistical difference in the normalization rate of PSI–assisted versus MI TKA.

Conclusion

Kinetics of CRP in MI arthroplasty are identical to the published kinetics of conventional TKA. Most patients normalize CRP at 3 weeks; however, 18 % does not by 6 weeks. This is not a sign of early prosthetic joint infection. Peak values are significantly lower for UKA but not for PSI TKA.

Level of evidence

II.     

Wertigkeit der diffusionsgewichteten MRT in der Beurteilung von Knochenmarkveränderungen bei Wirbelkörpermetastasen

Aim of the study. The aim of the study was the evaluation of the diffusion coefficient (ADC) of vertebral metastasis and regular vertebral bodies with diffusion weighted MRI (DWI). DWI evaluates the tissue-specific molecular diffusion of protons. In tissues with high cell densities (neoplasm) a decreased ADC can be expected due to restricted diffusion according to an exaggerated amount of intra- and intercellular membranes (i. e. diffusion barriers). Methods. In 5 breast cancer patients the ADC of both known vertebral metastases and of adjacent regular vertebral bodies were measured with DWI (1.0 T; Phased-Array-Body-Coil; b: 880 and 440 s/mm²). Results. The ADC of regular vertebral bodies (1.3±0.23×10^–,3s/mm²) was significantly (p≤0.0002) higher than in vertebral metastases (0.39±0.11×10^–3s/mm²). Conclusions. These data demonstrate that the ADC can be reliably measured in vertebral bodies. The quantitative evaluation of the ADC in vertebral bodies seems to be an objective and comparable parameter for differentiating malign from benign vertebral tissue.     

Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products

We identified two new-type cannabimimetic quinolinyl carboxylates, quinolin-8-yl 1-pentyl-(1H-indole)-3-carboxylate (QUPIC, 1) and quinolin-8-yl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate (QUCHIC, 2); and two new cannabimimetic carboxamide derivatives, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (ADB-FUBINACA, 3) and N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indole-3-carboxamide (ADBICA, 4), as designer drugs in illegal products. Compound 3 was reported to have a potent affinity for cannabinoid CB₁ receptor by Pfizer in 2009, but this is the first report of its detection in illegal products. No chemical or pharmacological data for compounds 1, 2, and 4 have appeared until now, making this the first report on these compounds. We also detected synthetic cannabinoids, APICA N-(5-fluoropentyl) analog (5), APINACA N-(5-fluoropentyl) analog (6), UR-144 N-(5-chloropentyl) analog (7), JWH-122 N-(5-chloropentyl) analog (8), and AM-2201 4-methoxynaphthyl analog (4-MeO-AM-2201, 9) herein as newly distributed designer drugs in Japan. It is of interest that compounds 1 and 2 were detected with their synthetic component, 8-quinolinol (10). A stimulant thiophene analog, α-pyrrolidinovalerothiophenone (α-PVT, 11), and an opioid receptor agonist, 3,4-dichloro-N-([1-(dimethylamino)cyclohexyl]methyl)benzamide (AH-7921, 12), were also detected as new types of designer drugs coexisting with several synthetic cannabinoids and cathinone derivatives in illegal products.     

Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone and a naphthoylindole 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201) found in illegal products obtained via the Internet and their cannabimimetic effects evaluated by in vitro [35S]GTP��S binding assays

During our careful surveillance of unregulated drugs in January to February 2011, we found two new compounds used as adulterants in herbal products obtained via the Internet. These compounds were identified by liquid chromatography?Cmass spectrometry, gas chromatography-mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The first compound identified was a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone (1), which is a positional isomer of (4-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone (RCS-4, 4). The second compound was 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201, 2). The compound 2 has been reported to be a cannabinoid receptor agonist. Because the cannabimimetic effects of compounds 1 and 4 have not been reported to date, their biological activities were evaluated by measuring the activation of [³⁵S] guanosine-5??-O-(3-thio)-triphosphate binding to guanine nucleotide-binding proteins, together with those of other synthetic cannabimimetic compounds. For quantitation of the above two compounds (1 and 2) and previously identified compounds (AM-694, 3; JWH-122, 5; RCS-4, 4), each product was extracted with methanol under ultrasonication to prepare a sample solution for analysis by liquid chromatography with ultraviolet detection. Each of four commercial products contained some of cannabimimetic indoles 1?C5; their contents ranged from 14.8 to 185 mg per pack.     

Two new synthetic cannabinoids, AM-2201 benzimidazole analog (FUBIMINA) and (4-methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone (MEPIRAPIM), and three phenethylamine derivatives, 25H-NBOMe 3,4,5-trimethoxybenzyl analog, 25B-NBOMe, and 2C-N-NBOMe, identified in illegal products

Two new types of synthetic cannabinoids, an AM-2201 benzimidazole analog (FUBIMINA, 1) and (4-methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone (MEPIRAPIM, 2), and three newly emerged phenethylamine derivatives, 25B-NBOMe (3), 2C-N-NBOMe (4), and a 25H-NBOMe 3,4,5-trimethoxybenzyl analog (5), were detected in illegal products distributed in Japan. The identification was based on liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–mass spectrometry (GC–MS), high-resolution MS, and nuclear magnetic resonance analyses. Different from the representative synthetic cannabinoids, such as JWH-018, which have a naphthoylindole moiety, compounds 1 and 2 were completely new types of synthetic cannabinoids; compound 1 had a benzimidazole group in place of an indole group, and compound 2 had a 4-methylpiperazine group in place of the naphthyl group. Compounds 3 and 4 were N-o-methoxybenzyl derivatives of 2,5-dimethoxyphenethylamines (25-NBOMe series), which had been previously detected in European countries, but have newly emerged in Japan. Compound 5 had an N-trimethoxybenzyl group in place of an N-o-methoxybenzyl group. Data on the chemistry and pharmacology of compounds 1, 2, and 5 have never been reported to our knowledge.     

Identification of a new synthetic cannabinoid in a herbal mixture: 1-butyl-3-(2-methoxybenzoyl)indole

Two unknown cannabimimetic compounds were detected in a seized herbal mixture after gas chromatography–mass spectrometry (GC–MS) screening. To elucidate the chemical structures, 0.3 g of the dried plant material was extracted with methanol and concentrated under reduced pressure. The extract was purified by silica gel column chromatography with methylene chloride and methanol. Pure compounds were isolated by preparative high-performance liquid chromatography (HPLC) and then analyzed by electrospray ionization (ESI) mass spectrometry (MS) with direct flow injection, high-resolution ESI-time-of-flight (TOF)–MS and one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. GC–MS spectra showed that the base ion at m/z 321 for compound 1 was the same as that of 1-pentyl-3-(4-methoxybenzoyl)indole (RCS-4), and the fragment ions were almost the same as those of RCS-4. The GC–MS spectrum of compound 2 was very similar to that of compound 1 except that the mass numbers of the fragment ions at m/z 290, 200, 186, and 173 of compound 2 were equally smaller than those of compound 1 by 14 amu. From these GC–MS results, compound 1 was assumed to be the 2- or 3-methoxy isomer of RCS-4, and compound 2 was assumed to be a 1-butylindole homologue of compound 1. The ESI mass spectra showed a single peak at m/z 322.33 for compound 1 and a single peak at m/z 308.25 for compound 2, which showed the masses of the protonated ions. High-resolution TOF–MS spectra showed the accurate mass numbers of protonated molecular ions at m/z 322.180512 for compound 1 and at m/z 308.164895 for compound 2, suggesting the molecular formulas of C₂₁H₂₃NO₂ and C₂₀H₂₁NO₂, respectively. The ¹H NMR spectra showed signals that suggested 23 and 21 protons for compounds 1 and 2, respectively, while the respective ¹³C NMR spectra showed 21 and 20 carbon signals. All protons and carbons were assigned by their couplings and correlations observed in ¹H–¹H correlation spectroscopy (COSY), ¹H–¹³C heteronuclear multiple bond correlation (HMBC), and ¹H–¹³C heteronuclear single quantum coherence (HSQC) spectra. On the basis of the spectral data, compound 1 was identified as the 2-methoxy isomer of RCS-4; compound 2 was identified for the first time as 1-butyl-3-(2-methoxybenzoyl)indole. Phenazepam and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) were also identified as coexisting drugs in the herbal mixture. The contents of compounds 1 and 2 in the mixture were calculated to be 22.4 and 3.45 mg/g, respectively.     

T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice

Objectives

To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice.

Methods

AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n?=?26) or 45 min (severe AKI, n?=?23). Sham animals served as controls (n?=?9). Renal histology was assessed in the acute (day 1?+?day 7; d1?+?d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined.

Results

Renal histology showed severe tubular injury at d1?+?d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138?±?2 % vs. 121?±?3 %, p?=?0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r?=?0.83).

Conclusion

T1-mapping non-invasively detects AKI severity in mice and predicts further outcome.

Key Points

? Renal T1-relaxation times are increased after ischemia-induced acute kidney injury. ? Renal T1-values correlate with subsequent kidney volume loss. ? T1-mapping detects the severity of acute kidney injury and predicts further outcome.     

Indicators for longterm survival after the transjugular portosystemic intrahepatic shunt procedure

Introduction. Complications of portal hypertension can be treated effectively by the transjugular intrahepatic portosystemic shunt procedure (TIPS). Indicators for long time survival after TIPS implantation are presented. Patients and Methods. From September 1992 until May 1995 forty-two consecutive patients (26 male, 16 female) with liver cirrhosis complicated by variceal bleeding (n = 27) or refractory ascites (n = 15) were treated by TIPS implantation and followed up clinically in a prospective, open study. The follow up period range was 5–3278 days. Univariate and multivariate regression analyses were applied to determine the correlation between patient characteristics and long term survival after TIPS implantation. The indicators were dichotomized at the median. The outcome variable was dichotomized. Positive outcome was defined as survival longer than three years without liver transplantation, all other outcomes were regarded as negative. Survival rates were determined for all patients and for subgroups according to results of the regression analyses. Results. During follow-up liver transplantation was performed in 8 of the 42 patients. 29 patients died. Mean survival was 1440 (±1060) days. Survival after one, two, three and six years was 76% (n = 32), 69%(n = 29), 62% (n = 26) and 38% (n = 16), respectively. The multivariate regression analysis revealed a significant better survival related to a prothrombine time >70%, MEGX synthesis >30 μg/l, and ICG clearance <13 min. Patients with high ICG clearance (OR = 1.9), high MEGX synthesis (OR = 5.0) or high prothrombine time scores (OR = 5.2) had a significantly longer survival. This survival advantage increased with follow up time. Conclusion. Longterm survival after TIPS implantation is influenced by the initial liver function. This survival advantage increases during follow up and is most pronounced after 6 years.     

Synthesis and basic evaluation of 7α-(3-[<Superscript>18</Superscript>F]fluoropropyl)-testosterone and 7α-(3-[<Superscript>18</Superscript>F]fluoropropyl)-dihydrotestosterone

Objective

7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[¹⁸F]fluoropropyl)-testosterone ([¹⁸F]7) and 7α-(3-[¹⁸F]fluoropropyl)-dihydrotestosterone ([¹⁸F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.

Methods

We synthesized [¹⁸F]7 and [¹⁸F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-³H]-methyltrienolone ([³H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).

Results

7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC₅₀ value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [¹⁸F]7 and [¹⁸F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [¹⁸F]15 is observed in the ventral prostate. [¹⁸F]7 and [¹⁸F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.

Conclusion

[¹⁸F]15 is better than [¹⁸F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [¹⁸F]15 in prostate might be insufficient for in vivo visualization. Although [¹⁸F]7 and [¹⁸F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[¹⁸F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[¹⁸F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [¹⁸F]15, in terms of net prostate uptake and in vivo metabolic stability.

     

Chemical constituents and DNA sequence analysis of a psychotropic herbal product

In recent years, the distribution of a variety of psychotropic products, especially “spice” and “herbal blends,” which are advertised to have narcotic-like effects, has become more widespread in the Japanese illegal drug market. We recently found two synthetic annabinoids, cannabicyclohexanol and JWH-018, that serve as adulterants in herbal products purchased via the Internet. In this study, we focused on a herbal product being sold as incense, which showed unknown components by liquid chromatography-mass spectrometry (LC-MS). The product did not show any peak corresponding to the above synthetic cannabinoids, but seven other peaks were identified by high-performance liquid chromatography and LC-MS. We identified them as N-methyltyramine (1), (R)-normacromerine (2), (R)-macromerine (3), (S)-vasicine (4), mescaline (5), harmaline (6), and harmine (7) by polarimetry, LC-MS, gas chromatography-mass spectrometry, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. We also used DNA sequence analyses to identify the plant species of the product. As a result of the sequencing of trnL-F, internal transcribed spacer (ITS), and rpl16 intron regions, three sequences derived from Coryphantha macromeris (Cactaceae), Peganum harmala (Zygophyllaceae), and Turnera diffusa (Turneraceae) were observed. Compounds 2 and 3, both phenethylamines, were reported to cause hallucinogenic effects and are frequently found in Coryphantha genus (Cactaceae). Therefore, the plant source of these compounds was considered to be C. macromeris. Compound 5 is known to be a psychoactive phenethylamine found in peyote (Lophophora williamsii) and San Pedro cactus (Trichocereus pachanoi). The β-carboline alkaloids 6 and 7 are known to be found in the seeds of P. harmala. Therefore, there seems to be no contradiction between the chemical constituents and the plant species estimated by DNA analyses, except for compound 5. This is the first report dealing with identification of the psychoactive cactus C. macromeris and its constituent compounds in a herbal product distributed in the illegal drug market.     

The C-reactive protein level after total knee arthroplasty is gender specific

Purpose

Laboratory diagnostics are part of the routine before and after operations. In all specialist surgical disciplines, including orthopaedic surgery, the acute-phase protein CRP is used to detect inflammatory processes, especially infections. The potential influence of patient gender on the postoperative course of CRP after TKA implantation is still unclear. In order to achieve a more precise evaluation of the complication-free general CRP course after TKA, the objective of the present study is to test the hypothesis that the p.o. course and level of CRP is gender specific in the first 10 days after TKA.

Methods

A total of 1068 consecutive patients who had been treated with a unilateral primary cemented total knee replacement due to primary osteoarthritis of the knee over a 36-month period were retrospectively included in the study. For all patients, the preoperative CRP value and the postoperative course of CRP from postoperative days 1–10 were recorded and tested for gender specificity.

Results

On days 2–5 and 7–8 after surgery, men had significantly higher CRP values than women. The maximum difference was 45 mg/L on the fourth p.o. day (men 170 mg/L, women 125 mg/L, p = 0.019).

Conclusion

The present study was able to show, for the first time, that the complication-free course of CRP in the first 10 days after TKA implantation is gender specific. The impact of the finding on diagnostic is that the gender-specific CRP course provides a more precise evaluation of the complication-free course of CRP after TKA. These results have clinical relevance to the interpretation of postoperative CRP values in order to avoid unnecessary investigations such as puncture or surgical care in female and male patients with uncomplicated TKA. Level of evidence Diagnostic study, III.

     

Preclinical evaluation of BAY 1075553, a novel 18F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer

Purpose

Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[¹⁸F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel ¹⁸F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor.

Methods

The ¹⁸F-radiolabelled stereoisomers of 2-[¹⁸F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553.

Results

BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 mSv/MBq. Non-clinical safety studies did not show off-target activity, effects on vital organs function or dose-dependent adverse effects.

Conclusion

BAY 1075553 was identified as a promising PET tracer for PSMA-positive prostate tumours in preclinical studies. BAY 1075553 can be produced using a robust, direct radiosynthesis procedure. Pharmacokinetic, toxicology and safety pharmacology studies support the application of BAY 1075553 in a first-in-man microdose study with single i.v. administration.     

Short-term side-effects of brain MR examination at 7 T: a single-centre experience

Objective

To study patient tolerability of brain imaging that employs an ultrahigh field (7 T) MR system

Methods

We examined 180 subjects that underwent brain MR examination at 7 T. A tolerability test consisting of two parts (during patient table motion and during the examination) was administered to all subjects in order to monitor their discomfort. The scores range from 0 to 5 for the first part, and from 0 to 10 for the second part, the total score of each subject therefore ranging from 0 (no side effects reported) to 15 (lowest tolerability)

Results

A total of 51 % of subjects reported at least one side effect but all were mild in intensity and did not require examination interruption. No serious adverse event was reported. The total score (mean ± standard deviation) was 1.1?±?1.5 out of 15 (mean score 0.4?±?0.7 out of 5 during patient table motion and 0.7?±?1.1 out of 10 during MR). Patient discomfort was not related to gender or health status, but it was reduced with time after system installation with increasing operator experience in performing UHF MR examinations.

Conclusions

Ultrahigh field MRI is well tolerated without excessive discomfort to subjects.

Key Points

? 7-T MRI is well tolerated with low incidence of side effects ? The subjects’ discomfort during 7-T MRI is reduced as the operators’ experience increases ? 7-T MRI is practicable in healthy subjects and patients with neurodegenerative diseases