A Damp-and-Push Technique for the Copolymer (Onyx) Embolization of Dural Arteriovenous Fistula

BackgroundCopolymer (Onyx) embolization is an effective treatment for dural arteriovenous fistula (dAVF), however, some dAVFs have multiple, high-flow feeding vessels, resulting in insufficient embolization. For the treatment of such patients, we have developed a novel flow-control technique, the ‘damp-and-push technique’. The purpose of this study was to evaluate the technical efficiency and safety of this technique.MethodsSeven patients who had been diagnosed with intracranial dAVF were treated by transarterial Onyx embolization using the damp-and-push technique between 2016 and 2019. This technique was designed to reduce blood flow to the shunt site using a balloon catheter in the major feeding vessel other than the one injected with Onyx, leading to better Onyx penetration and enabling more controlled embolization of complex dAVFs. Retrospectively collected data were reviewed to assess the occlusion rates and clinical outcomes.ResultsThe dAVF was at a transverse sinus-sigmoid sinus junction in four patients, in the superior sagittal sinus in two, and in the tentorium in one. Five cases were Cognard type Ⅱb and two cases were Cognard type Ⅳ. All the patients were treated by transarterial Onyx injection via the main feeding vessel, combined with flow reduction in the other main feeding vessel using a balloon catheter. Complete occlusion was achieved in six patients and elimination of cerebral venous reflux was achieved in all the patients. There were no immediate or delayed post-interventional complications.ConclusionsTransarterial Onyx embolization of dAVF using the damp-and-push technique is safe and yields a high complete occlusion rate.     

Reduction of toxicity in brachytherapy using a new technique

PurposeThe purpose of the study was to elucidate the usefulness of a dose evaluation method for reducing late genitourinary (GU) toxicity in high-dose-rate brachytherapy (HDR-BT) of prostate cancer.Methods and MaterialsGU toxicity was scored in accordance with the Common Terminology Criteria for Adverse Events version 4.0. The prostatic urethra was divided into three segments (base = B, midgland = M, apex = A), which were subclassified into seven subgroups (B, M, A, BM, BA, MA, BMA) using a D_10% color map of the urethra. Significance testing was conducted on urethral D_0.1% and D_10% among the seven subgroups. Grade < 2 GU toxicity was also implemented.ResultsData of 174 patients with localized prostate cancer treated with HDR-BT combined with external beam radiotherapy between November 2011 and July 2014 were analyzed retrospectively. Median age was 74 (53–84) years, and median followup period was 44 (6–69) months. The number of Grade < 2 and Grade ≥ 2 toxicity was significantly different in the M subgroup than in the other subgroups (p < 0.05), suggesting increased radioresistance in the midgland urethra.ConclusionsA high-dose-area evaluation method using a urethral D_10% color map may be helpful in reducing late GU toxicity in HDR-BT for prostate cancer.     

Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency

Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age.Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas.Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 β-oxidation activity was dramatically reduced.Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient’s fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.     

Lyssavirus surveillance in bats of southern China’s Guangxi Province

Although rabies virus is widely distributed in the world, and has been the subject of extensive investigations with the objective of its ultimate prevention, control, and management, there is much less knowledge of the characteristics, distribution, and infectivity of other lyssaviruses. Since bats are known animal vectors for all but one of the known lyssavirus genotypes, we have performed an extensive survey of bats in the Guangxi Province to provide information on lyssavirus distribution in southern China. The lyssavirus nucleoprotein gene was detected in brains of 2.86 % of 2,969 bats. Nucleotide sequence homologies among isolates were 86.9–99.6 %, but only 70.0–85.0 % for lyssaviruses in GenBank. These infected bats were detected from a wide area, essentially forming a band running from the south-west to the north-east of Guangxi, and it appears that infection by new lyssaviruses is widespread in this region.     

Optimized scan delay for late hepatic arterial or pancreatic parenchymal phase in dynamic contrast-enhanced computed tomography with bolus-tracking method

Objectives:To determine the optimal scan delay corresponding to individual hemodynamic status for pancreatic parenchymal phase in dynamic contrast-enhanced CT of the abdomen.Methods:One hundred and fourteen patients were included in this retrospective study (69 males and 45 females; mean age, 67.9 ± 12.1 years; range, 39–87 years). These patients underwent abdominal dynamic contrast-enhanced CT between November 2019 and May 2020. We calculated and recorded the time from contrast material injection to the bolus-tracking trigger of 100 Hounsfield unit (HU) at the abdominal aorta (s) (Time_TRIG) and scan delay from the bolus-tracking trigger to the initiation of pancreatic parenchymal phase scanning (s) (Time_SD). The scan delay ratio (SDR) was defined by dividing the Time_SD by Time_TRIG. Non-linear regression analysis was conducted to assess the association between CT number of the pancreas and SDR and to reveal the optimal SDR, which was ≥120 HU in pancreatic parenchyma.Results:The non-linear regression analysis showed a significant association between CT number of the pancreas and the SDR (p < 0.001). The mean Time_TRIG and Time_SD were 16.1 s and 16.8 s, respectively. The SDR to peak enhancement of the pancreas (123.5 HU) was 1.00. An SDR between 0.89 and 1.18 shows an appropriate enhancement of the pancreas (≥120 HU).Conclusion:The CT number of the pancreas peaked at an SDR of 1.00, which means Time_SD should be approximately the same as Time_TRIG to obtain appropriate pancreatic parenchymal phase images in dynamic contrast-enhanced CT with bolus-tracking method.Advances in knowledge:The hemodynamic state is different in each patient; therefore, scan delay from the bolus-tracking trigger should also vary based on the time from contrast material injection to the bolus-tracking trigger. This is necessary to obtain appropriate late hepatic arterial or pancreatic parenchymal phase images in dynamic contrast-enhanced CT of the abdomen.     

Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics

Stereoselective and efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction. The synthetic isosteres can be used in Fmoc-based solid phase peptide synthesis, resulting in the preparation of the 14-mer RGG peptidomimetics containing an (E)-methylalkene or a (Z)-chloroalkene unit.

An efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction.

Glycylglycine (Gly-Gly) is the smallest dipeptide and has been synthesized by many approaches in the last 100 years.¹ Due to its versatile nature and ready availability, glycylglycine has been used as a chemical probe² and buffer³ in biochemical studies and also as a reagent which can enhance the solubility of overexpressed proteins.⁴ In addition to the utility of Gly-Gly itself, oligoglycine (oligo-Gly) motifs are notable for being more flexible and less-functionalized than any combination of other amino acids. These features are useful in bioconjugation strategies which link multiple biomolecules without interfering with the function of each biomolecule, allowing synthesis of bioconjugated artificial molecules including dimeric, multi-domain, and fusion proteins.⁵ The flexibility of oligo-Gly enables the formation of unusual secondary structures of peptides and proteins.⁶ Thus, the oligo-Gly motif can be found in the biologically important peptides and proteins such as Met/Leu-enkephalin ( and ), the C-terminus of ubiquitin , ctenidin,⁷ shepherin I,⁸ and DNA/RNA-binding proteins with repeated sequences related to the various physiological processes via protein–protein and protein–nucleic acids interactions.⁹ These proteins relate with gene expression, DNA damage signal and apoptosis, however, the detail effects of Gly-Gly with steric and electronic factors to these functions are unknown. Given the importance of oligo-Gly in various fields, non-hydrolyzable peptidomimetics of oligo-Gly could be attractive building blocks for the synthesis of novel bioconjugated molecules and complex peptidomimetics with improved chemical stability and functionality. For example, even the Gly-Gly dipeptide mimic with the tetra-substituted alkene unit replacing the Gly-Gly peptide bond has been shown to promote the β-hairpin formation, and is thus the smallest peptidomimetic that is known to control a peptide structure.¹⁰ There are two reports of the synthesis of Gly-Gly-type fluoroalkene dipeptide isosteres.¹¹ However, the poor synthetic access to such molecules has hindered their application to the peptidomimetics. Our long-standing interest in the drug discovery with amide-to-alkene isosteric switching prompted this investigation into the stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres.In this report, we describe the beginning of our oligo-Gly-based peptidomimetic study with the stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their use in Fmoc-based solid phase peptide synthesis (SPPS). In the first application of isosteres of this type to access complex peptidomimetics, we synthesize 14-mer RGG peptidomimetics containing (E)-methylalkene or (Z)-chloroalkene unit as surrogates for a Gly-Gly peptide bond. These two isosteres were selected because the potentials of both isosteres have not been fully uncovered, though there are several promising examples.^12,13 Since the carbonyl oxygen equivalents of those isosteres are similar in their size¹⁴ but differ in their electronic properties,¹⁵ comparative studies of these isosteres would have the advantage of exploring the role of peptide bonds in terms of their steric and electronic natures. This work also uncovered the unique ability of the Gly-Gly-type (Z)-chloroalkene isostere to induce β-turn structures in the almost unfoled peptides (Fig. 1).Open in a separate windowFig. 1Gly-Gly peptide and its alkene-type peptidomimetics.The main challenges in this study include the stereoselective formation of the (E)-methylalkene and (Z)-chloroalkene moieties as the surrogates of the Gly-Gly trans-peptide bond, together with the control of the olefine isomerization under the condition of the isostere synthesis and Fmoc-based SPPS. There are several synthetic approaches toward tri-substituted alkene-type isosteres, including the Overman rearrangement,¹³ the S_N2′-type opening of alkenylaziridines,^12a Cu-mediated CF₃-coupling of vinyl iodide,¹⁶ and cross-couplings of vinyl stannane.¹⁷ Organocuprate-mediated reactions of α,β-unsaturated carbonyl compounds with γ-leaving group(s) are also powerful methods to produce tri-substituted alkene-type isosteres, and are particularly suitable for the stereoselective synthesis of (Z)-fluoroalkene¹⁸ and (Z)-chloroalkene isosteres.¹⁹The preparation of Gly-Gly-type alkene dipeptide isosteres was facilitated by the organocuprate-mediated SET reduction that was used in the stereoselective formation of the (E)-methylalkene and (Z)-chloroalkene moieties. Scheme 1 shows the synthesis of (E)-methylalkene isosteres (5). A Witting reaction of methacrolein (1) with ethyl (triphenylphosphoranylidene)acetate followed by epoxidation with m-CPBA afforded the alkenyl oxirane (2) which, treated with Gillman reagent (n-Bu₂CuLi), produced the allylic alcohol (3) with high E-selectivity. A Mitsunobu reaction of 3 with Ns(Boc)NH and deprotection provided the Gly-Gly-type (E)-methylalkene dipeptide isostere 5 that can be applied to the Fmoc-based SPPS. All reactions leading to the synthesis of 5 were performed on a gram scale.Open in a separate windowScheme 1Synthesis of Gly-Gly-type (E)-methylalkene dipeptide isosteres (5).Synthesis of chloroalkene isostere (14) is shown in Scheme 2. Based on previous results for the successful, efficient synthesis of Val-Xaa-type chloroalkene isosteres,^19c we assumed that a similar protocol would allow for the synthesis of 14. However, our attempts revealed that the Gly substrate used has different reactivity and selectivity compared to the other substrates, particularly in the SET reduction step. Consequently, Gly-specific reaction conditions are necessary. The nucleophilic addition of the lithium enolate of methyl dichloroacetate to the N-sulfinylaldimine (7), prepared from (±)-tert-butylsulfinamide (6) and paraformaldehyde and m-CPBA oxidation of 6 gave the N-tert-butylsulfonyl (Bus)-protected α,α-dichloro-β-amino ester (8). Precise control of the amount of DIBAL-H at low temperatures enables the partial reduction of 8, and this is followed by a Horner–Wadsworth–Emmons reaction to produce the corresponding (E)-enoate (9). Initial efforts to apply our established conditions for SET reduction with Me₂CuLi identified the poor Z-selectivity of the reaction and also its propensity to form the α-methylated side products 11 and 12 (Open in a separate windowScheme 2Synthesis of Gly-Gly-type (Z)-chloroalkene dipeptide isosteres (14).Reactivity of (E)-enoate (9) with organocuprates^a

Laparoscopy-assisted repair with Ventralex ST Hernia Patch for a small subcostal hernia: A case report

A 55-year-old woman with a history of right hepatic lobectomy via a Benz incision presented for evaluation of a new abdominal bulge in the right upper quadrant. We diagnosed an incisional hernia, but because we could neither reduce the hernia contents nor locate the orifice, we performed a laparoscopic evaluation. Laparoscopy revealed subcostal herniation of the greater omentum via a 2-cm defect on the caudal side of the right ribs, which we repaired using a Ventralex ST Hernia Patch. Laparoscopic placement of this mesh with straps allowed for reliable deployment, fixation, and confirmation of defect closure, including the cranial aspect—often a major challenge in subcostal hernia repair.     

Evaluation of four commercial severe acute respiratory coronavirus 2 antibody tests

IntroductionNumerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests exists commercially; however, their performance using clinical samples is limited. Although insufficient to detect SARS-CoV-2 in the early phase of infection, antibody assays can be of great use for surveillance studies or for some coronavirus disease 2019 (COVID-19) patients presenting late to the hospital.MethodsThis study evaluated the sensitivity and specificity of four commercial SARS-CoV-2 lateral flow antibody tests using 213 serum specimens from 90 PCR-positive confirmed COVID-19 patients. Of 59 negative control sera, 50 were obtained from patients with other respiratory infectious diseases before COVID-19 pandemic began while nine were from patients infected with other respiratory viruses, including two seasonal coronaviruses.ResultsThe varied sensitivities for the four commercial kits were 70.9%, 65.3%, 45.1%, and 65.7% for BioMedomics, Autobio Diagnostics, Genbody, and KURABO, respectively, between sick days 1 and 155 in COVID-19 patients. The sensitivities of the four tests gradually increased over time after infection before sick day 5 (15.0%, 12.5%, 15.0%, and 20.0%); from sick day 11–15 (95.7%, 87.2%, 53.2%, and 89.4%); and after sick day 20 (100%, 100%, 68.6%, and 96.1%), respectively. For severe illness, the sensitivities were quite high in the late phase after sick day 15. The specificities were over 96% for all four tests. No cross-reaction due to other pathogens, including seasonal coronaviruses, was observed.ConclusionsOur results demonstrated the large differences in the antibody test performances. This ought to be considered when performing surveillance analysis.