Direct use of 1,3-dienes for the allylation of ketones via catalytic hydroindation

In this study, in situ catalytically generated allylic indium from 1,3 dienes and InCl₂H was developed for use in the allylation of ketones. This protocol resulted in the unprecedented establishment of a successive combining of quaternary C–C bonds, which could then be applied to many types of ketones. Other branched 1,3 dienes and vinyl cyclopropanes, could also be coupled with ketones in a reaction where CuH would not be applicable.

In this study, in situ catalytically generated allylic indium from 1,3 dienes and InCl₂H was developed for use in the allylation of ketones.

Homoallylic alcohols are useful building blocks in the synthesis of bioactive natural compounds and pharmaceuticals. For these syntheses, the preparation of tertiary compounds has remained challenging regardless of whether or not they are given asymmetrically.¹ The allylation of ketones with allylic reagents is a typical method for the preparation of these compounds (Scheme 1a).² This method, however, cannot avoid wasteful steps such as the transmetalation between Grignard reagents and B, Si or Sn sources and the reductive generation between allylic halides and low-valent metals. Although this method can be applied to highly stereocontrolled reactions, the wasteful steps are cumbersome and more practical reaction methods are required.Open in a separate windowScheme 1Synthesis of homoallylic alcohols from allylation reagents with ketones.For this process, 1,3-dienes are an important industrial feedstock that is produced on a massive scale via either the cracking of ethylenes or the transformation of biomass. Easily available dienes have recently replaced the conventional allylation of aldehydes with the aid of transition metal catalysts (Scheme 1b).³ After the first application using a Ti catalyst by Gendre and Moïse,⁴ Krische has expanded the field with the introduction of Ru-catalyzed stereocontrolled reactions.⁵ Other transition metals such as Ni,⁶ Ir,⁷ and Rh⁸ have contributed to improvements in coupling. A recent adoption of ketones as viable substrates was achieved by Liu and Buchwald via proficient Cu–H chemistry.⁹ The scope of possible substrates could be expanded even further,¹⁰ however, particularly with the use of 1,3-dienes and ketones that possess a variety of functional groups.Our group has explored the hydrostannylation¹¹ or indation¹² of unsaturated bonds in the preparation of reactive organostannanes or indiums that could be applied to further transformations, although stoichiometric amounts of Sn or In sources must be added to the reaction systems. Recently, a transition metal-free reductive coupling of 1,3-dienes,¹³ or their derivatives such as vinyl cyclopropanes,¹⁴ with aldehydes catalyzed by Bu₂SnXH has been developed, but the method would not allow the use of ketones due to the low reactivity of the reaction intermediate, allylic stannanes (Scheme 1c). On the other hand, our group has already developed a process for the hydroindation of 1,3-dienes with a stoichiometric amount of InX₂H to give allylic indiums followed by the allylation of ketones.^12b,12d Herein, we report the catalytic coupling of 1,3-dienes or vinyl cyclopropanes with ketones through the generation of allylic indiums via the hydroindation of 1,3-dienes with a catalytic amount of InX₂H (Scheme 1c).We initiated the optimization of the reaction conditions by combining 1,3-butadiene (1a) and acetophenone (2a) in a sealed test tube (13 The desired product 3aa was obtained in a 92% yield as a mixture of the diastereomers (entry 1). The yield was lowered either when no MeOH was used or when the reaction time was cut by half (entries 2 and 3). A screening of the silanes showed that MePhSiH₂ was the optimal hydride source (entries 4–7). We found that the reaction was finished in 3 h when the reaction temperature was raised to 60 °C (entry 8). Replacing the solvent with MeCN, Et₂O or toluene did not improve the reaction yield (entries 9–11). It was necessary to add NaOMe to the reaction system for a facile generation of InCl₂H (entry 12).¹⁶ It was important to add InCl₃ to the reaction (entry 13). A radical scavenger, TEMPO, suppressed the progress of the reaction, which implied that this reaction contains a radical process (entry 14). The reaction yield was decreased when the lower amount of the catalyst was employed (entry 15).Optimization of the reaction conditions^a

Flash effect of contrast microbubbles by ultrasound exposure

Background Microbubbles used in contrast echo examination are destroyed by exposure to ultrasound but develop a new ultrasound wave on destruction; the so-called flash effect. Factors influencing the magnitude of the new wave have yet to be elucidated. Here we investigate the method of assessing this effect and attempt to clarify the relevant differences between contrast agents. Methods Three contrast agents were used: Albunex, Optison (FS 069), and Levovist. We used fundamental mode (3.75 MHz) and harmonic mode (2.5 to 5.0 MHz) ultrasound produced by a prototype echocardiograph (Toshiba) and measured the video intensity (VI) (256 gray scale) of each contrast agent contained in a thin rubber sack while changing acoustic power from a minimum level to high levels of +10.5 dB +16.5 dB, and +22.5 dB. Results VI was not changed by low acoustic power; however, it increased rapidly for a short time and then decreased rapidly when exposed to high acoustic power. The increase in VI varied with acoustic power: 30 to 60 at +10.5 dB and 70 to 115 at +22.5 dB. The increase in VI was larger in harmonic mode than in fundamental mode. The degree of decrease in VI after the flash effect correlated with the extent of increase in VI produced by the flash effect. Conclusions The flash effect occurred with each of the contrast agents, and its magnitude varied with acoustic power and contrast agent.     

Outcomes After Intensive Rehabilitation for Mechanically Ventilated Patients: A Nationwide Retrospective Cohort Study

ObjectiveTo examine the effects of intensive rehabilitation on mortality and liberation from mechanical ventilation among patients with mechanical ventilation in intensive care units.DesignRetrospective cohort study using the Diagnosis Procedure Combination inpatient database.SettingPatients discharged from acute care hospitals from April 2010 to March 2016.ParticipantsPatients (N=46,438) aged 20 years and older who were admitted to intensive care units and who started rehabilitation within 3 days of starting mechanical ventilation.InterventionIntensive rehabilitation in intensive care unit in the first 5 days after admission. Amount of rehabilitation was defined as the average number of units per day in the first 5 days after admission and was dichotomized as intensive (≥1.0 unit/d) or nonintensive (<1.0 unit/d) rehabilitation.Main Outcome MeasuresThe primary outcome was in-hospital mortality. The secondary outcome was liberation from mechanical ventilation.ResultsWe identified 29,982 eligible patients, including intensive (n=7745) and nonintensive (n=22,237) rehabilitation groups. In the propensity score-matched analysis, the intensive rehabilitation group had significantly lower in-hospital mortality (risk difference: ?3.4%; 95% CI, ?4.9% to ?1.9%) and a higher proportion of liberation from mechanical ventilation (subdistribution hazard ratio, 1.08; 95% CI, 1.03-1.13) compared with the nonintensive rehabilitation group.ConclusionsPatients receiving a higher amount of rehabilitation in intensive care units were less likely to die and more likely to be liberated from mechanical ventilation.     

Hypoglossal canal dural arteriovenous fistula embolized under precise anatomical evaluation by selective intra-arterial injection computed tomography angiography

Dural arteriovenous fistula (DAVF) involving the hypoglossal canal is rare but increasingly reported. To achieve complete obliteration without a procedure-related complication, understanding of the precise anatomy of this DAVF is essential. Here, we describe a 72-year-old man who underwent selective intra-arterial injection computed tomography angiography which allowed us to understand the detailed anatomy of the complex DAVF regarding access routes and the target regions for transvenous embolization (TVE). With the aid of this novel neuroimaging technique successful target TVE was achieved safely and completely.     

Successful laparoscopic distal pancreatectomy for a large solid pseudopapillary neoplasm: A case report

A 30‐year‐old Japanese woman presented at our hospital with a pancreatic tumor. Contrast‐enhanced CT revealed a tumor with a 12‐cm diameter in the pancreatic body and tail. In the preoperative setting, endoscopic ultrasound‐guided fine‐needle aspiration permitted a histopathological diagnosis of solid pseudopapillary neoplasm. Twhe patient underwent laparoscopic distal pancreatectomy with splenectomy. Our procedure involved three steps. Firstly, the splenic artery was occluded to block inflow of blood to the tumor. Then, we transected the neck of the pancreas using radical antegrade modular pancreatosplenectomy. Finally, hand‐assisted laparoscopic surgery allowed us to secure the operating field and easily handle the large tumor. This enabled us to accomplish laparoscopic distal pancreatectomy, and en‐bloc resection was completed. The patient was discharged without major complications. Laparoscopic distal pancreatectomy for huge solid pancreatic tumors can be completed safely.     

Secondary glioblastomas with IDH1/2 mutations have longer glioma history from preceding lower-grade gliomas

Isocitrate dehydrogenase (IDH)1/2 mutations have been proposed as a genetic marker for secondary glioblastoma (sGBM). This study aimed to evaluate the impact of the IDH1/2 mutations on the clinical course and genetic alterations of sGBMs, which histopathologically progressed from lower-grade gliomas. We investigated 18 sGBMs, including 8 sGBMs with IDH1/2 mutations (sGBM-Mut) and 10 with wild-type IDH1/2 (sGBM-Wt). The median overall survival time of patients with sGBM-Mut was significantly longer than that of patients with sGBM-Wt (68.2 vs. 25.3 months). The median time from initial diagnosis to sGBM diagnosis was also significantly longer for sGBM-Mut than for sGBM-Wt (50.1 vs. 13.4 months). There was no difference in the median survival time from the sGBM diagnosis between sGBM-Mut and sGBM-Wt (6.75 vs. 6.8 months). All sGBM-Mut (7 of 7) and 6 of 9 sGBM-Wt had TP53 mutations, and the remaining one-thirds of sGBM-Wt had neither TP53 mutations nor 1p/19q codeletion. These observations suggest that IDH1/2 mutations have an impact on the glioma history of sGBM with different genetic pathway. The aggressive progression to sGBM-Wt suggest the need for more intense treatment to the IDH1/2 wild-type tumors.     

Long Survival of a Small-Cell Lung Cancer Patient Who Received Maintenance Chemotherapy with Irinotecan

Lung cancer is the leading cause of cancer-related death worldwide. Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. It is characterized by rapid tumor growth and early metastasis to multiple organs. Response to initial chemotherapy is generally good; however, the majority of patients develop recurrence and the prognosis of such patients is reportedly 2–4 months. Evolution of the treatment for SCLC has stagnated, and cisplatin + etoposide has been the standard chemotherapy for decades. Meanwhile, the combination of cisplatin + irinotecan has demonstrated equivalent efficacy to cisplatin + etoposide. Recently, maintenance chemotherapy has been extensively investigated in non-small-cell lung cancer (NSCLC), and is currently recommended as a standard treatment in clinical guidelines. On the contrary, a maintenance strategy has not been established for SCLC. Here, we describe an SCLC patient who received maintenance chemotherapy with irinotecan for more than 2 years after induction chemotherapy with cisplatin + irinotecan, and survived long term with no recurrence.Key Words: Small-cell lung cancer, Irinotecan, Maintenance, Long survivor, Extensive disease     

Influence of body mass index and total testosterone level on biochemical recurrence following radical prostatectomy

Objective: A high body mass index (BMI) and a low testosterone level wererecently reported to be prognostic factors for prostate-specificantigen (PSA) recurrence following radical prostatectomy (RP).The goal of this study was to clarify their relationship andinfluences on biochemical recurrence after RP. Methods: We analysed 126 patients whose data, including the pre-operativeBMI and pre-operative serum total testosterone level, were available.All patients underwent RP at our institution between March 1998and April 2006 without any adjuvant therapy or pelvic lymphnode metastasis. The Cox proportional hazards model was usedfor the multivariate analysis regarding PSA recurrence for thevariables of age, operation period, BMI, clinical stage, PSA,Gleason's sum, pre-operative serum total testosterone leveland margin status. Results: There were no internal correlations among the parameters weused, even between BMI and the total testosterone level. Thetotal testosterone level was not different between two BMI groups(BMI <26.4 and 26.4 kg/m²: the cut-off is the mean + 1 SD).BMI, PSA and Gleason's sum were found to be independent predictorsfor PSA recurrence through the multivariate analysis. PSA recurrence-freesurvival rates at 2 years were 77% for BMI <26.4 kg/m², and31% for BMI 26.4 kg/m² (P = 0.002, log-rank test, 95% CI: 1.489–7.726). Conclusions: The current study suggests that high BMI independently contributesto PSA recurrence but that the total testosterone level doesnot. Although the mechanism by which obesity promotes PSA recurrencein RP patients has not been established, careful observationis needed for patients with high BMI.