The Formosalides: Structure Determination by Total Synthesis.

Total synthesis allowed the constitution of the cytotoxic marine macrolides of the formosalide family to be confirmed and their previously unknown stereostructure to be assigned with confidence. The underlying blueprint was inherently modular to ensure that each conceivable isomer could be reached. This flexibility derived from the use of strictly catalyst controlled transformations to set the stereocenters, except for the anomeric position, which is under thermodynamic control; as an extra safety measure, all stereogenic centers were set prior to ring closure to preclude any interference of the conformation adopted by the macrolactone rings of the different diastereomers. Late-stage macrocyclization by ring-closing alkyne metathesis was followed by a platinum-catalyzed transannular 6-exo-dig hydroalkoxylation/ketalization to craft the polycyclic frame. The side chain featuring a very labile unsaturation pattern was finally attached to the core by Stille coupling.

Chagosensine: A Riddle Wrapped in a Mystery Inside an Enigma.

The marine macrolide chagosensine is supposedly distinguished by a (Z,Z)-configured 1,3-chlorodiene contained within a highly strained 16-membered lactone ring, which also incorporates two trans-2,5-disubstituted tetrahydrofuran (THF) rings; this array is unique. After our initial synthesis campaign had shown that the originally proposed structure is incorrect, the published data set was critically revisited to identify potential mis-assignments. The "northern" THF ring and the anti-configured diol in the "southern" sector both seemed to be sites of concern, thus making it plausible that a panel of eight diastereomeric chagosensine-like compounds would allow the puzzle to be solved. To meet the challenge, the preparation of the required building blocks was optimized, and a convergent strategy for their assembly was developed. A key role was played by the cobalt-catalyzed oxidative cyclization of alken-5-ol derivatives ("Mukaiyama cyclization"), which is shown to be exquisitely chemoselective for terminal alkenes, leaving even terminal alkynes (and other sites of unsaturation) untouched. Likewise, a palladium-catalyzed alkyne alkoxycarbonylation reaction with formation of an α-methylene-γ-lactone proved instrumental, which had not found application in natural product synthesis before. Further enabling steps were a nickel-catalyzed "Tamaru-type" homocrotylation, stereodivergent aldehyde homologations, radical hydroindation, and palladium-catalyzed alkyne-1,2-bis-stannation. The different building blocks were assembled in a serial fashion to give the idiosyncratic chlorodienes by an unprecedented site-selective Stille coupling followed by copper-mediated tin/chlorine exchange. The macrolactones were closed under forcing Yamaguchi conditions, and the resulting products were elaborated into the targeted compound library. Yet, only one of the eight diastereomers turned out to be stable in the solvent mixture that had been used to analyze the natural product; all other isomers were prone to ring opening and/or ring expansion. In addition to this stability issue, our self-consistent data set suggests that chagosensine has almost certainly little to do with the structure originally proposed by the isolation team.

The importance of pancreatic inflammation in endosonographic diagnostics of solid pancreatic masses.

AIMS: Endosonography (EUS) is one of the main diagnostic tools for the differential diagnosis of pancreatic masses. The aim of our study was to describe the value of this technique in the work-up of solid pancreatic lesions, considering the influence of the morphological evidence of pancreatic inflammation in the diagnostic process. MATERIAL AND METHODS: Retrospective analysis of prospectively collected data in our tertiary University center. From March 2007 to October 2015, 218 patients underwent EUS for a suspected solid pancreatic neoplasm (based on previous cross-sectional imaging results, idiopatic acute pancreatitis, weight loss, pancreatic hyperenzymemia, painless jaundice or elevated Ca 19-9 values). RESULTS: Malignant lesions were diagnosed in 98 (45%) patients. Sensitivity of EUS for malignancy was 91% and specificity 89.2%. Signs of pancreatic inflammation in the surrounding pancreatic parenchyma around the focal lesion were present in 97 patients (44.4%)(more often in men, smokers and drinkers, and the most common etiology was focal chronic pancreatitis) and in these patients the sensitivity and sensibility dropped to 44% and 87.1%, respectively. In patients without signs of pancreatic inflammation, the pancreatic focal lesions were adenocarcinoma, neuroendocrine tumor, ventral/dorsal split, non-pancreatic pathology, pancreatic lipomatosis and autoimmune pancreatitis. CONCLUSION: Pancreatic inflammation (either focal or involving the whole gland) lowers the diagnostic sensibility of EUS in the work- up of pancreatic masses suspected for cancer, requiring further invasive diagnostic methods. Focal autoimmune pancreatitis and paraduodenal pancreatitis are still confused with pancreatic cancer, even in the absence of pancreatic inflammation.

Enantioselective Synthesis of des-Epoxy-Amphidinolide N.

The synthesis of des-epoxy-amphidinolide N was achieved in 22 longest linear and 33 total steps. Three generations of synthetic endeavors are reported herein. During the first generation, our key stitching strategy that highlighted an intramolecular Ru-catalyzed alkene-alkyne (Ru AA) coupling and a late-stage epoxidation proved successful, but the installation of the α,α'-dihydroxyl ketone motif employing a dihydroxylation method was problematic. Our second generation of synthetic efforts addressed the scalability problem of the southern fragment synthesis and significantly improved the efficiency of the atom-economical Ru AA coupling, but suffered from several protecting group-based issues that proved insurmountable. Finally, relying on a judicious protecting group strategy together with concise fragment preparation, des-epoxy-amphidinolide N was achieved in a convergent fashion. Calculations disclose a hydrogen-bonding bridge within amphidinolide N. Comparisons of 13C NMR chemical shift differences using our synthetic des-epoxy-amphidinolide N suggest that amphidinolide N and carbenolide I are probably identical.

Total Synthesis of Putative Chagosensine.

The marine macrolide chagosensine is the only natural product known to date that embodies a Z,Z-configured chloro-1,3-diene unit. This distinguishing substructure was prepared by a sequence of palladium-catalyzed 1,2-distannation of an alkyne precursor, regioselective Stille cross-coupling at the terminus of the resulting bisstannyl alkene with an elaborated alkenyl iodide, followed by chloro-destannation of the remaining internal site. The preparation of the required substrates centered on cobalt-catalyzed oxidative cyclization reactions of hydroxylated olefin precursors, which allowed the 2,5-trans-disubstituted tetrahydrofuran rings, embedded into each building block, to be formed with excellent selectivity. The highly strained macrolactone could ultimately be closed under forcing Yamaguchi conditions. Comparison of the spectral data of the synthetic sample with those of authentic chagosensine methyl ester confirmed that the structure of this intriguing compound has been mis-assigned by the isolation team.

Rhodium-Catalyzed Diastereoselective Cyclization of Allenyl-Sulfonylcarbamates: A Stereodivergent Approach to 1,3-Aminoalcohol Derivatives.

A diastereoselective and stereodivergent rhodium-catalyzed intramolecular coupling of sulfonylcarbamates with terminal allenes is described and it provides selective access to 1,3-aminoalcohol derivatives, scaffolds found in bioactive compounds. The reaction is compatible with a large range of different functional groups, thus furnishing products with high diastereoselectivities and yields. Moreover, multigram scale reactions, as well as the application of suitable product transformations were demonstrated.

Peripheral intravenous power injection of iodinated contrast media: the impact of temperature on maximum injection pressures at different cannula sizes.

RATIONALE AND OBJECTIVES: Modern computed tomographic scanners and examination protocols often require high injection rates of iodinated contrast media (CM). The purpose of this study was to investigate the maximum injection pressures (MIPs) with different CM at different temperatures in the most common intravenous cannula (IVC) sizes. MATERIALS AND METHODS: Three IVC sizes, 22, 20, and 18 gauge, were evaluated. All examinations were performed with a pressure-limited (300 psi) power injector. The MIPs of three different CM (Solutrast 300, Imeron 350, and Imeron 400) were measured at room temperature (20 degrees C) and at 37 degrees C using increasing flow rates (1-9 mL/s). The intactness of the IVCs was checked after injection. RESULTS: Heating the CM led to reductions in injection pressures (P < .001). Using constant flow rates, the difference in MIP between 20-gauge and 22-gauge IVCs was higher than that between 20-gauge and 18-gauge IVCs. By heating the CM, the manufacturer's suggested operating pressure limit was exceeded at higher flow rates, such as with an 18-gauge cannula at 8 mL/s instead of 6 mL/s using warmed iomeprol 400. Even with pressures of up to 159.7 psi, none of the IVCs ruptured. CONCLUSIONS: Heating of CM effectively reduces MIPs using power injection in common IVCs. Although the manufacturer's suggested MIP was exceeded at higher flow rates, safe CM injection seems to be possible even in small cannulas using power injection. The compilation of the obtained data is meant to serve as guidance for future decisions on parameters of the power injection of iodinated CM.

Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials.

PURPOSE: To compare the nephrotoxicity of iso-osmolar iodixanol with that of nonionic low-osmolar contrast media (CM) (LOCM) in randomized clinical trials. MATERIALS AND METHODS: This meta-analysis was conducted with a systematic search of MEDLINE, EMBASE, BIOSIS, Web of Science, ISI Web of Knowledge, Current Contents Medizin, Cochrane Library (until August 2007), trial registers, conference proceedings, and reference lists to identify studies and with requests from all manufacturers of CM for unidentified studies. Randomized controlled trials assessing serum creatinine levels before and after intravascular application of iodixanol or LOCM were included. The primary outcome measures were the incidence of contrast medium-induced nephropathy (CIN) and change in serum creatinine levels. RESULTS: Twenty-five trials were included. Iodixanol did not significantly reduce the risk of CIN (relative risk [RR], 0.80; 95% confidence interval [CI]: 0.61, 1.04; weighted mean difference in serum creatinine increase, 0.01 mg/dL [0.88 mumol/L]; 95% CI: -0.01, 0.03). There was no significant risk reduction after intravenous administration of the CM (RR, 1.08; 95% CI: 0.62, 1.89); subgroup with preexisting renal insufficiency (RR, 1.07; 95% CI: 0.56, 2.02) or after intraarterial administration (RR, 0.68; 95% CI: 0.46, 1.01); subgroup with preexisting renal insufficiency (RR, 0.59; 95% CI: 0.33, 1.07). However, in patients with intraarterial administration and renal insufficiency, the risk of CIN was greater for iohexol than for iodixanol (RR, 0.38; 95% CI: 0.21, 0.68), whereas there was no difference between iodixanol and the other (noniohexol) LOCM (RR, 0.95; 95% CI: 0.50, 1.78). CONCLUSION: Iodixanol is not associated with a significantly reduced risk of CIN compared with the LOCM pooled together. However, in patients with intraarterial administration and renal insufficiency, iodixanol is associated with a reduced risk of CIN compared with iohexol, whereas no significant difference between iodixanol and other LOCM could be found.

[Suggestions for prevention of adverse reactions after intravasal administration of iodinated contrast media]. / Empfehlungen zur Prophylaxe der Nebenwirkungen bei intravasaler Applikation jodhaltiger Kontrastmittel. Suggestions for prevention of adverse reactions after intravasal administration of iodinated contrast media.

Iodinated contrast media are widely used in computed tomography and angiography. Adverse reactions such as contrast-medium induced nephropathy (CIN), anaphylactoid reactions and iodine-induced thyrotoxicosis are associated with intravasal administration of contrast agents. Iodinated contrast agents are generally considered to be safe, but in rare cases they can cause severe life threatening situations. In this review we present an overview about the incidence, pathways, and risk factors of adverse reactions. Simple schemes including hydration protocols for prevention of CIN, medication for prophylaxis of iodine-induced thyrotoxicosis with thyreostatics and anaphylactoid reactions with histamine antagonists and corticosteroids are suggested.

[Diagnosis of fungal pneumonia in the thoracic CT]. / Diagnose der Pilzpneumonie in der Thorax-CT CT scan findings of fungal pneumonia.

The importance of fungal infection of the lung in immunocompromised patients has increased substantially during the last decades. Numerically the most patients are those with neutropenia, e.g., patients with malignancies or solid organ and stem cell transplantation, chemotherapy, corticosteroid use and HIV infection. Although fungal infections can occur in immunocompetent patients, their frequency in this population is rare. The clinical symptoms such as fever accompanied with non-productive cough are unspecific. In some patients progression to hypoxemia and dyspnea may occur rapidly. In spite of improved antifungal therapy morbidity and mortality of these infections are still high. Therefore an early and non-invasive diagnosis is very important. That is why CT and even better High-Resolution-CT (HR-CT) is a very important modality in examining immunocompromised patients with a probability of fungal infection. CT is everywhere available and, as a non-invasive method, able to give the relevant diagnose efficiently. This paper should give an overview about the radiologic findings and possible differential diagnosis of diverse pulmonary fungal infections in CT. Pneumonias caused by Aspergillus, Cryptococcus, Candida, Histoplasma, Mucor and Geotrichum capitatum are illustrated.

[Differential diagnosis of focal lesions of the kidney in CT and MRT]. / Differentialdiagnose fokaler Nierenläsionen in CT und MRT.

The great majority of renal masses are found incidentally as a result of the use of ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI). If ultrasonography is not diagnostic CT or MRI should be initiated to differentiate lesions of the kidney that need surgical intervention from those that do not and from those that need follow-up examinations. Cystic renal masses are characterized by using the Bosniak classification, including category IIF. In solid Lesions of the kidney first non-surgical lesions as well as lymphoma, renal infarction and nephritis should be excluded. Identifying fatty components in renal lesions is very important because in angiomyolipoma they are almost always present. CT and MRI are exellent for tumor detection. Careful evaluation of imaging finding combined with the patient's history should assist the radiologist in making the proper diagnosis or recommending the appropriate treatment in most cases. This article provides a review about renal masses, the imaging methods for their evaluation and their characteristic features at CT and MR imaging. Different lesions are demonstrated like xantogranulomatous pyelonephritis, acute pyelonephritis, renal infarction, lymphoma, angiomyolipoma, renal oncocytoma, cystic lesion and polycystic disease the kidney, echinococcosis, renal cystadenoma, metastases, renal cell carcinoma (RCC), and multiple bilateral RCC in patients with Hippel-Lindau-Syndrome. This article should help to differentiate complex cystic lesions of the kidney by using the Bosniak-classification, especially Bosniak Category IIF. Solid masses should be characterized and the major question to be answered is whether the mass represents a surgical or nonsurgical lesion or if follow-up studies are necessary.

Extraosseous manifestation of multiple myeloma with unusual appearance in computed tomography--case report.

Extramedullary Localizations at diagnosis or during the course of multiple myeloma are rare. We report on a 70 year old patient, presenting multiple hypoechoic liver lesions during an ultrasound examination. The following contrast-enhanced computed tomography demonstrated hypodense liver Lesions with slight contrast enhancement and hyperdense polypoid masses in the wall of the gall bladder as well as a small pericostal tumor. A punch biopsy of the liver and immunohistochemical studies confirmed the diagnosis of extramedullary multiple myeloma. In a follow-up CT five weeks later the liver lesions and the pericostal tumor clearly showed progress, the masses in the gall bladder had developed into a concentric wall-thickening. Additionally, polypoid contrast-enhancing masses in the gastric wall became apparent as well as a hypodense lesion in the spleen. Radiologists should be aware that multiple myeloma can on rare occasions present as hypodense nodules in the liver or new masses in other organs in CT. Because of the morphologic similarity to metastatic disease, a biopsy may be necessary for definitive diagnosis.

Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Usual interstitial pneumonia (UIP) is the histopathological pattern identifying patients with the clinical entity of IPF. Despite aggressive immunosuppressive therapy the clinical course is usually dismal. For selected patients only lung transplantation improves prognosis and quality of life. After lung transplantation patients often receive a potent cyclosporine-based immunosuppressive therapy. Some reports suggest that cyclosporine has the potential to prevent progression of fibrosis. OBJECTIVE: In patients with single lung transplantation (sLTx) for UIP we evaluated the effect of cyclosporine-based immunosuppressive therapy on progression of fibrosis using a high-resolution computed tomography (HRCT) scoring system. METHODS: This retrospective observational study included 13 patients (24-64 years old) with histologically confirmed UIP who had HRCT scans preceding and following sLTx and who survived at least 6 months after sLTx. All patients were initially treated with cyclosporin A, prednisone and azathioprine. Three radiologists analyzed HRCT scans by setting a score regarding fibrosis [fibrosis score (FS); range 0-5 for each lobe] and ground-glass opacity [ground-glass score (GGS); range 0-5 for each lobe]. A comparison of serial changes (interval: 12-96 months posttransplant, 2-4 HRCT examinations/patient) was performed with the sign test. RESULTS: Mean pretransplant FS and GGS of the nontransplanted lung were 1.80 and 1.61, respectively. Comparing pre- and posttransplant HRCT scans, mean lung FS significantly increased (0.35 +/- 0.15/year; p = 0.00024), while GGS tended to decrease (0.06 +/- 0.26/year; p = 0.5). CONCLUSION: A cyclosporin A based triple immunosuppressive regimen following sLTx does not seem to prevent progression of the fibrotic changes of the native lung in patients with IPF.

Reversibility and time-dependency of contrast medium induced inhibition of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) conversion in renal proximal tubular cells in vitro: comparison of a monomeric and a dimeric nonionic iodinated contrast medium.

OBJECTIVES: To evaluate the time-course and reversibility of toxicity of a low-osmolar and an iso-osmolar radiographic contrast medium on renal tubular cell cultures. MATERIALS AND METHODS: LLC-PK1-cells were incubated with iomeprol, iodixanol, and mannitol (4.7-75 mg I/mL, 2-24 hours). Metabolic activity was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide-(MTT) assay. RESULTS: Iomeprol and iodixanol induced a time- and dose-dependent inhibition of MTT conversion (75%-19% and 70%-23% of control for iomeprol and iodixanol, respectively, at concentrations ranging from 4.7 to 75 mg I/mL after an incubation time of 2 hours and 64%-14% and 65%-12% of control after 24 hours). The mannitol induced inhibition of the MTT conversion was significantly weaker than that induced by iomeprol (99%-47% of control at concentrations corresponding to 4.7-75 mg I/mL after an incubation time of 24 hours, P < 0.001). After 24 hours incubation with iomeprol, iodixanol, or mannitol and a recovery time of 2 hours after removal of the test-solutions, there was only a small inhibition of MTT-conversion (89%, 88%, and 95% of control at 75 mg I/mL). CONCLUSIONS: Contrast medium induced cytotoxicity consisted of a reversible part and an irreversible part. There was no difference in cytotoxicity between iomeprol and iodixanol over a broad range of concentrations and incubation-times.

Cytotoxicity of iodinated and gadolinium-based contrast agents in renal tubular cells at angiographic concentrations: in vitro study.

PURPOSE: To test in vitro whether gadolinium-based contrast agents induce fewer toxic effects on renal tubular cells than does an iodinated contrast medium at concentrations used for angiography. MATERIALS AND METHODS: LLC-PK1 cells were incubated with iomeprol, gadopentetate dimeglumine, gadobenate dimeglumine, gadoterate meglumine, gadodiamide, and corresponding mannitol solutions for 24 hours at 37 degrees C in two experimental settings: measurements with equally attenuating solutions and measurements with equimolar solutions. Cytotoxicity was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, trypan blue testing, and an assay to detect apoptosis and necrosis. Data were analyzed with analyses of variance and post hoc tests. RESULTS: Yielding the same x-ray attenuation, iomeprol-300 and iomeprol-150 at concentrations of 2.34-18.75 mg of iodine per milliliter induced significantly (P < .001) lower inhibition of MTT conversion (74%-102% of undamaged control cells) compared with 15.63-125.00 mmol/L concentrations of the gadolinium-based agents (mean percentages of undamaged control cells: 48%-80%, 50%-87%, 60%-95%, and 56%-92% with gadopentetate dimeglumine, gadobenate dimeglumine, gadoterate meglumine, and gadodiamide, respectively). At equimolar concentrations (62.5 mmol/L), iomeprol-190 induced a mean extent of inhibition of MTT conversion (69% of undamaged control cells) similar to that induced by gadoterate meglumine (71%) and gadodiamide (70%), whereas gadopentetate dimeglumine and gadobenate dimeglumine induced stronger effects (63% and 64%, respectively; P < .001). At trypan blue testing, there were more dead cells after incubation with 125 mmol/L gadopentetate dimeglumine than after incubation with iomeprol-190 (57% vs 19%, P < .001). The 125 mmol/L gadopentetate and gadobenate formulations induced more necrosis and apoptosis than did gadoterate meglumine, gadodiamide, and iomeprol (mean percentage difference between treated and untreated control cells: for necrosis, +124%, +95%, +17%, -6%, and +3%, respectively; for apoptosis, +34%, +35%, +13%, +4%, and +5%, respectively; P < .001). CONCLUSION: At angiographic concentrations, gadolinium-based contrast agents do not induce fewer cytotoxic effects on cultured renal tubular cells than does iomeprol.

[Retention of a videoendoscopy capsule leading to small bowel obstruction in a patient with recurrence of rectum carcinoma]. / Dünndarmobstruktion durch Retention einer Videoendoskopie-Kapsel bei einem Patienten mit Rektumkarzinomrezidiv.

Wireless capsule endoscopy has become the most sensitive and most specific diagnostic modality for evaluation of the mucosa of the small bowel and is increasingly used by gastroenterologists. The most important complication is retention of the video capsule in patients with pre-existing strictures of the small bowel. We report on a case of a 73-year-old man who underwent capsule endoscopy because of obscure gastrointestinal bleeding. The capsule was retained in the ileum leading to small bowel obstruction during the following days. Surgery demonstrated that the capsule had been retained in a segment of the ileum which was infiltrated by a recurrence of rectum carcinoma. Radiologists should know this complication of capsule endoscopy as well as the relative importance of the radiographic techniques for evaluating the small bowel, which possibly could predict a free passage of the video capsule.

[Differential diagnosis of bronchiectasis: high-resolution CT as a valuable aide]. / Differenzialdiagnose der Bronchiektasen: High-resolution CT als wertvolle Hilfe.

Bronchiectasis is defined as localized irreversible dilatation of the bronchial tree. Brochiectasis has been associated with a wide variety of causes, but it is mostly caused by acute, chronic or recurrent infections. This paper should give a review about the manifestation of bronchiectasis and bronchioloectasis in HR-CT and discuss the causing entities. However, integration of bronchiectasis and other HR-CT findings may enable a narrower differential diagnosis, in some cases it is possible to give the correct diagnose directly.

[Nevoid basal cell carcinoma syndrome]. / Naevoid Basalzellkarzinom-syndrom.

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal-dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar/plantar pits, calcification of the falx cerebri, and spine and rib anomalies. The combination of clinical, imaging, and histological findings is helpful in identifying NBCCS patients. Imaging plays a crucial role in evaluation of these patients. We present a wide variety of clinical and radiological findings characteristic of this disease.