Photoredox/Copper-Catalyzed One-Pot Aminoalkylation/Cyclization of Alkenes with Primary Amines to Synthesize Polysubstituted γ-Lactams.

Visible-light-driven chemical transformation has emerged as a powerful tool for the synthesis of γ-lactams. However, during this transformation, the α-bromoimides need to be pre-prepared. Herein, we report a photoreodox/copper-catalyzed one-pot three-component reaction of alkenes with primary amines for the construction of γ-lactams. In this transformation, the orthoquinones were generated via a photocatalytic pathway, followed by attack by Cu-amido complexes and intramolecular cyclization to give the γ-lactams. This method represents a simple synthetic route displaying broad functional group tolerance, including substrates bearing alcohols, ketones, heterocycles, esters, halides, alkynes, nitriles, ethers, etc.

DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis.

Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.

A Comparative Study of the Effects of Electronic Cigarette and Traditional Cigarette on the Pulmonary Functions of C57BL/6 Male Mice.

INTRODUCTION: Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms. METHODS: A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells. RESULTS: Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS: The findings of the present study indicate that the safety of E-cig should be further evaluated. IMPLICATIONS: Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.

Quercetin prevents bone loss in hindlimb suspension mice via stanniocalcin 1-mediated inhibition of osteoclastogenesis.

Recent studies demonstrate that diet quercetin (Quer) has obvious bone protective effects on ovariectomized rodents but thus far there is no direct evidence to support the inhibitory effect of Quer on bone loss caused by long-term unloading. In the present study, we investigated whether Quer could prevent bone loss induced by unloading in mice. Mice were subjected to hindlimb suspension (HLS) and received Quer (25, 50, 100 mg· kg-1 ·day-1, ig) for 4 weeks. Before euthanasia blood sample was collected; the femurs were harvested and subjected to MicroCT analysis. We showed that Quer administration markedly improved bone microstructure evidenced by dose-dependently reversing the reduction in bone volume per tissue volume, trabecular number, and bone mineral density, and the increase of trabecular spacing in mice with HLS. Analysis of serum markers and bone histometric parameters confirmed that Quer at both middle and high doses significantly decreased bone resorption-related markers collagen type I and tartrate-resistant acid phosphatase 5b, and increased bone formation-related marker procollagen 1 N-terminal propeptide as compared with HLS group. Treatment with Quer (1, 2, 5 µM) dose-dependently inhibited RANKL-induced osteoclastogenesis through promoting the expression of antioxidant hormone stanniocalcin 1 (STC1) and decreasing ROS generation; knockdown of STC1 blocked the inhibitory effect of Quer on ROS generation. Knockdown of STC1 also significantly promoted osteoclastogenesis in primary osteoclasts. In conclusion, Quer protects bones and prevents unloading-caused bone loss in mice through STC1-mediated inhibition of osteoclastogenesis. The findings suggest that Quer has the potential to prevent and treat off-load bone loss as an alternative supplement.

Expert consensus on image-guided radiofrequency ablation of pulmonary tumors: 2018 edition.

Lung cancer ranks first in incidence and mortality in China. Surgery is the primary method to cure cancer, but only 20-30% of patients are eligible for curative resection. In recent years, in addition to surgery, other local therapies have been developed for patients with numerous localized primary and metastatic pulmonary tumors, including stereotactic body radiation therapy and thermal ablative therapies through percutaneously inserted applicators. Percutaneous thermal ablation of pulmonary tumors is minimally invasive, conformal, repeatable, feasible, cheap, has a shorter recovery time, and offers reduced morbidity and mortality. Radiofrequency ablation (RFA), the most commonly used thermal ablation technique, has a reported 80-90% rate of complete ablation, with the best results obtained in tumors < 3 cm in diameter. Because the clinical efficacy of RFA of pulmonary tumors has not yet been determined, this clinical guideline describes the techniques used in the treatment of localized primary and metastatic pulmonary tumors in nonsurgical candidates, including mechanism of action, devices, indications, techniques, potential complications, clinical outcomes, post-ablation surveillance, and use in combination with other therapies. In the future, the role of RFA in the treatment of localized pulmonary tumors should ultimately be determined by evidence from prospective randomized controlled trials comparing sublobar resection or stereotactic body radiation therapy.

A Case Series of Liver Abscess Formation after Transcatheter Arterial Chemoembolization for Hepatic Tumors.

BACKGROUND: Liver abscess is a serious complication following transcatheter arterial chemoembolization (TACE). Much attention has been paid to this condition as it may interfere with the treatment process and result in a poor prognosis of the patient. This study aimed to analyze the causes of liver abscess, a complication, after TACE for hepatic tumors and to summarize management approaches. METHODS: From June 2012 to June 2014, of 1480 consecutive patients who underwent TACE at our hospital, five patients developed liver abscess after TACE procedures for hepatic tumors. Of the five patients, each receiving conventional TACE, one underwent three sessions, two underwent two sessions, and the remaining two underwent one session of TACE. Demographic and clinical characteristics, together with management approaches and prognosis, were collected through a review of medical records. RESULTS: These five patients were confirmed to have post-TACE liver abscess through clinical manifestations, laboratory, and imaging tests. After percutaneous drainage and anti-inflammatory treatments, the symptoms present in four patients with liver abscess significantly improved as evidenced by shrinkage or disappearance of the abscess cavity, and the patients recovered completely after sufficient drainage. The remaining patient experienced recurrent symptoms and abdominal abscess, achieved no significant improvement after treatment, and eventually died of severe infection and multiple organ failures. CONCLUSIONS: TACE must be implemented with extreme caution to avoid liver abscess. An effective management relies on an early diagnosis, prompt use of sufficient doses of appropriate antibiotics, and active implementation of abscess incision, drainage, and aspiration.

Radix Dipsaci total saponins stimulate MC3T3-E1 cell differentiation via the bone morphogenetic protein-2/MAPK/Smad-dependent Runx2 pathway.

Radix Dipsaci total saponins (RTS) are primary active components of Radix Dipsaci, which is administered orally for the treatment of osteoporosis according to Chinese Medicine. RTS have also been shown to reduce the risk of bone fractures in rats. However, the detailed molecular mechanisms underlying their action remain elusive. In the present study, the ability of RTS to increase alkaline phosphatase activity, osteocalcin levels and the degree of mineralization was investigated in MC3T3­E1 mouse osteoblast precursor cells. In addition, the associated molecular mechanism was detected. The results revealed that RTS exerted an effect on osteoblastic maturation and differentiation. Induction of differentiation by RTS was associated with an increase in the expression levels of bone morphogenetic protein­2 (BMP­2), phosphorylated (P)­Smad1/5/8, P­ERK1/2, P­p38 and Runt­related transcription factor 2 (Runx2). Blocking BMP­2 expression with noggin significantly reduced the levels of osteoblastic differentiation and subsequently attenuated the expression levels of P­Smad1/5/8, P­ERK1/2, P­p38 and Runx2. This indicated that RTS induced osteoblastic differentiation through BMP­2/mitogen­activated protein kinase/Smad1/5/8­dependent Runx2 signaling pathways and that it may be a promising agent for enhancing bone formation.

The importance of the prenyl group in the activities of osthole in enhancing bone formation and inhibiting bone resorption in vitro.

Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-κB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects.

[Synthesis and antifatigue activities of new benzamide derivatives].

To explore novel antifatigue agents targeting with AMPA receptor, 10 compounds were synthesized and their structures were confirmed by 1H NMR, ESI-MS and elemental analysis. 1-BCP was treated as the leading compound. The antifatigue activities were evaluated by weight-loaded forced swimming test, and the AMPA receptor binding affinities were tested with radioligand receptor binding assays. The results unveiled that 5b appeared to possess potent antifatigue activities and high affinity with AMPA receptor, which deserved further studies.

Antiosteoporosis effect of radix scutellariae extract on density and microstructure of long bones in tail-suspended sprague-dawley rats.

Radix Scutellariae (RS), a medicinal herb, is extensively employed in traditional Chinese medicines and modern herbal prescriptions. Two major flavonoids in RS were known to induce osteoblastic differentiation and inhibit osteoclast differentiation, respectively. This study aimed to investigate the effect of Radix Scutellariae extract (RSE) against bone loss induced by mechanical inactivity or weightlessness. A hindlimb unloading tail-suspended rat model (TS) was established to determine the effect of RSE on bone mineral density and bone microarchitecture. Treatment of RSE at 50 mg/kg/day and alendronate (ALE) at 2 mg/kg/day as positive control for 42 days significantly increased the bone mineral density and mechanical strength compared with TS group. Enhanced bone turnover markers by TS treatment were attenuated by RSE and ALE administration. Deterioration of bone trabecula induced by TS was prevented. Moreover, both treatments counteracted the reduction of bone volume fraction, trabecular thickness and number, and connectivity density. In conclusion, RSE was demonstrated for the first time to prevent osteoporosis induced by TS treatment, which suggests the potential application of RSE in the treatment of disuse-induced osteoporosis.

A systematic review of the efficacy and pharmacological profile of Herba Epimedii in osteoporosis therapy.

The purpose of this systematic review is to assess the efficacy and pharmacological profiles of Herba Epimedii in osteoporosis therapy. Four databases were extensively retrieved that include two Chinese electronic databases (VIP Information and CNKI) and two English electronic databases (CA and MEDLINE). Herba Epimedii has been an important traditional herbal medicine for centuries in China and other Asian countries. Recently, quite a few pharmacological effects of Herba Epimedii, its extracts and active components have been identified that include improving bone health and cardiovascular function, regulating hormone level, modulating immunological function, and inhibiting tumor growth. The anti-osteoporosis activity of Herba Epimedii and its extracts have attracted world-wide attention. The literature search has revealed that a lot of studies have recently been carried out related to the bone-strengthening activity of Herba Epimedii and some of its active compounds, such as total flavonoids and icariin. Pharmacokinetic and toxicity studies have confirmed the efficacy and safety of Herba Epimedii and its most abundant active component icariin, while only a few authors have reviewed the anti-osteoporosis properties of the plants. So we summarize the work of various investigators on the effects of Herba Epimedii, its extracts and active components against osteoporosis. The underlying mechanism of osteoprotective action, derivatives of icariin, animal models and cell lines used in the research were also reviewed in this paper.

[Effects of naringin on proliferation, differentiation and maturation of rat calvarial osteoblasts in vitro].

OBJECTIVE: To investigate the effects of naringin on the proliferation, differention and maturaion of rat calvarial osteoblasts (ROB). METHOD: Segregated neonatal SD rat skull, enzyme digestion to obtain ROB. The culture medium was replaced every three days. Serial subcultivation proceeded when cells covered with 80% culture dish. Naringin supplemented into the culture at 1 x 10(-4), 1 x 10(-5), 1 x 10(-6), 1 x 10(-7) mol x L(-1) respectively. MTT method was adopted in proliferation analysis and the activity of ALP was examined after induced 9 days. Search the best concentration and supplemented into the medium, then the osteogenic differentiation markers including the secretion amount of osteocalcin, osteopontin and bone morphogenetic protein-2 were compared between the naringin-supplemented group and the control. Total RNA was isolated and the mRNA level of bFGF, IGF-1, Runx-2, Osterix, ERa and ERbeta was investigated by Real time RT-PCR. Total protein also was isolated and the expression ERa, ERbeta and collagen I was examined by Western blot. After the addition of ICI 182.780, an inhibitor of the estrogen signal pathway, these index also was examined and the changes were compared. RESULT: The ROB proliferation was motivated by naringin dose-dependently. And it evidently leads to osteogenic process and maturation. 1 x 10(-5) mol x L(-1) is the best concentration. Naringin improved the secretion of osteocalcin, osteopontin, bone morphogenetic protein-2 and collagen I significantly. Besides, it can also enhanced the mRNA level of bFGF, IGF-1, Runx-2, Osterix, ERalpha and ERbeta. While all these effects can be restrained by ICI 182.780. CONCLUSION: The naringin with final concentration of 1 x 10(-5) mol x L(-1) enhances the osteogenic differentiation and maturation of ROB significantly, while the promoting effects vanished after the addition of ICI 182.780. These results suggesting that naringin is one of the phytoestrogens and have the activity of bone formation may via estrogen signal pathway, it can be developed into a new drug for osteoporosis therapy.

Pharmacokinetic interactions among major bioactive components in Radix Scutellariae via metabolic competition.

Baicalein (B), wogonin (W) and oroxylin A (OA) are major components in Radix Scutellariae with similar pharmacokinetic properties. Due to the co-presence of these three flavones in herbal formulations for Radix Scutellariae, they are likely consumed together. The aim of this study is to investigate whether the pharmacokinetics of individual flavones is influenced by each other and the underlying mechanism of the interaction. Various systems were utilized in the current study including a rat in vivo study, a Caco-2 cell monolayer model and a rat in situ single-pass intestinal perfusion as well as in vitro enzymatic kinetics studies. The B, W and OA given singly as well as in a mixture were administered and the corresponding pharmacokinetic parameters were calculated and compared. After co-administration of the three flavones to rats, OA absorption increased significantly in comparison with when OA was administered alone. Mechanistic studies on the Caco-2 cell monolayer and rat in situ single-pass intestinal perfusion models revealed that co-administration of B, W and OA could significantly enhance their absorption and decrease the extent of phase II metabolism. Further in vitro enzymatic study and a transport study in transfected MDCK cells revealed that metabolic competition rather than membrane transporters might contribute to the pharmacokinetic interactions. The co-presence of multiple active components would result in metabolic interactions, which may induce further changes in pharmacodynamics.

In vitro and in situ evaluation of herb-drug interactions during intestinal metabolism and absorption of baicalein.

ETHNOPHARMACOLOGICAL RELEVANCE: Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (-)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models. MATERIALS AND METHODS: Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose-response curves were plotted and IC(50) values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb-drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples. RESULTS: It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites. CONCLUSIONS: Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb-drug and herb-herb interactions between B and selected compounds, especially CUR.

[Influence of adjuvant therapy on survival of patients with pancreatic carcinoma of body and tail: a report of 137 cases].

OBJECTIVE: To investigate the effect of adjuvant therapy on the treatment of carcinoma of the body and tail of pancreas. METHODS: The clinical data of 137 patients with carcinoma of the body and tail of pancreas, 91 males and 46 females, aged 58.9 (24 - 76), of which 38 underwent radical resection, 24 underwent palliative resection, and 75 did not undergo resection, and 58 of which underwent adjuvant therapy, were analyzed. RESULTS: The overall 3-year survival rate was 10.7% for the whole group, 27.3% for the radical resection group, 4.2% for the palliative resection, and 4.5% for the no resection group. The median survival time (MST) was 8 months for the whole group, 15 months for the radical resection group, 8 months for the palliative resection group, and 6 months for the no resection group. The 3-year survival rate was 13.9% for the patients undergoing adjuvant therapy and 7.2% for those without adjuvant therapy, and the MST was 11 months for those undergoing adjuvant therapy, and 5 months for those without adjuvant therapy. Intra-arterial therapy and radiation therapy were protective factors for those whose cancerous tissues were not radically resected (OR = 1.56, 95% CI: 1.04 - 2.35, P = 0.033). CONCLUSION: Adjuvant therapy significantly improves the survival of the patients with pancreatic carcinoma of the body and tail. The clinical effect of intra-arterial therapy is better than those of radiation therapy and chemotherapy.

Simultaneous determination of vitexin-4''-O-glucoside and vitexin-2''-O-rhamnoside from Hawthorn leaves flavonoids in rat plasma by HPLC method and its application to pharmacokinetic studies.

The present study was to investigate the pharmacokinetics of the two similar flavonoid glycosides, vitexin-4''-O-glucoside (VGL) and vitexin-2''-O-rhamnoside (VRH) in rats after intravenous administration of hawthorn leaves flavonoids (HLF). Blood samples were collected via tail vein at time intervals after drug administration and the plasma concentrations of the studied ingredients were analyzed by HPLC after the plasma protein was precipitated directly with methanol. VGL and VRH were successfully separated using a C(18) column with a UV detection at 330 nm and a mobile phase of methanol-acetonitrile-tetrahydrofuran-0.5% acetic acid (1:1:19.4:78.6, v/v/v/v). The assay linearities of VGL and VRH were confirmed over the range 0.23-138.42 and 0.36-218.49 microg/ml, respectively. The accuracy and precision of the two analytes at high, medium and low concentration were within the range of -3.13% to 3.51% and below 4%, the mean assay recoveries of them (n=5) ranged from 96.87% to 101.75% and 96.88% to 103.51% for intra- and inter-day assays and the mean extraction recoveries of them (n=5) varied from 92.68% to 95.74% for VGL and 93.45% to 99.26% for VRH, respectively. After intravenous administration of HLF to rats over the doses range of 10-40 mg/kg, the plasma concentration--time curves of VGL and VRH were both conformed to the three-compartment open pharmacokinetic model and linear pharmacokinetic characteristics.

[The pharmacokinetic study on cytarabine nanoparticle lyophilization injection in rabbits].

OBJECTIVE: The pharmacokinetics of Cytarabine Polybutylcyanoacrylate Nanoparticles (Ara-C-PBCA-NP) lyophilization injection in rabbits was studied. METHODS: Ara-C water solution was taken as reference, the concentration of Ara-C was determined by HPLC, and the pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetic properties of Ara-C water solution and Ara-C-PBCA-NP lyophilization injection complied with two-department model. The parameters t1/2 beta and MRT of Ara-C-PBCA-NP lyophilization injection were prolonged, and CL was reduced dramatically (P < 0.05). CONCLUSION: Ara-C-PBCA-NP lyophilization injection possesses prolonged retention time in vivo and significant sustained releasing character.

[Value of mixed embolus transarterial chemoembolization in the treatment of hepatocellular carcinoma].

OBJECTIVE: To investigate the value of transarterial chemoembolization (TACE) using mixed emboli for hepatocellular carcinoma (HCC). METHODS: 188 patients with HCC were divided into two groups according to the treatment modality: 103 patients in group A treated by routine iodine embolus agent; 85 patients in group B by mixed iodine embolus agent (ultra-liquified iodinized oil + gelatin sponge + chemotherapeutic agents). The pattern of the arrested iodine deposition in the tumor, response, resectability during follow-up, pathological changes, survival and complications in the two groups were analyzed and compared. RESULTS: The pattern of full-and-dense iodine deposition in the tumor and the response rate (CR + PR) were 59.2% and 32.0% in group A, 89.4% and 56.5% in group B. Surgical resection after TACE was possible in 5.8% (6/103) of group A versus 15.3% (13/85) of group B. Complete tumor necrosis was observed in 1.0% and 4.7% in groups A and B, respectively. 1-, 2- and 3-year actual survival rates were 57.7%, 42.8% and 8.4% in group A, and 79.8%, 55.3%, 38.5% in group B. The difference in results between the two groups was statistically significant, however, the incidence of complication in the two groups was similar. CONCLUSION: Transarterial chemoembolization with mixed iodine emboli is more effective than with the routine iodine emboli in the treatment of bulky or nodular hepatocellular carcinoma rich in blood supply. Mixed iodine emboli is tolerable without increase in severe complications.