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Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via S N 2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres. Due to the synthetic utility of the products, stereoselective halogenation is a powerful method for the synthesis of chiral compounds. Here the authors report an enantioselective decarboxylative chlorination, giving access to a range of α-chloroketones.

Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via SN 2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.

Background Cardiac tamponade is a rare postoperative complication of esophageal cancer surgery, which leads to rapid hemodynamic changes and can be fatal if not treated properly and promptly. Herein, we report a case of cardiac tamponade after thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstitution for esophageal cancer that was successfully treated with surgical drainage. Case presentation An 86-year-old man with lower thoracic esophageal cancer underwent thoracoscopic subtotal esophagectomy and retrosternal gastric tube reconstitution. No intra-operative complications were observed. On the first postoperative day, tachycardia and hypotension were observed, and pericardial effusion was identified on computed tomography images. The patient was diagnosed with obstructive shock secondary to cardiac tamponade. As percutaneous puncture drainage was not possible due to the presence of a retrosternal gastric tube, pericardiotomy with a small left anterior thoracotomy was performed, and a large amount of hematogenous fluid was drained, which instantly improved circulation. On the second postoperative day, the patient showed decreased pulse pressure, and computed tomography revealed a residual and enlarged hematoma around the right ventricle. The patient underwent surgical drainage and another pericardiotomy with a small right anterior thoracotomy was performed to drain the hematoma. At this time, multiple injuries to the fatty tissue, epicardium, and myocardium with active bleeding were observed on the anterior surface of the right ventricle near the root of the pulmonary artery. In this patient, the ascending aorta ran further to the right and dorsal sides than usual, causing the anterior wall of the right ventricle near the root of the pulmonary artery to be closer to the back of the sternum. This abnormality may have contributed to injury during the creation of the retrosternal pathway, leading to cardiac tamponade. Conclusions Cardiac tamponade after esophagectomy can occur because of manipulation during creation of the retrosternal route, with an anomaly in the aortic position being present in this case. Gentle manipulation and selection of the reconstruction route according to the patient’s condition are necessary in cases with such anatomical abnormalities.

Intracoronary acetylcholine (ACh) provocation test is useful to diagnose vasospastic angina. However, paroxysmal atrial fibrillation (AF) often occurs during intracoronary ACh provocation test, leading to disabling symptoms. The aim of this study was to investigate the incidence and predictors of paroxysmal AF during the test. A total of 377 patients without persistent AF who underwent intracoronary ACh provocation test were included. Paroxysmal AF during ACh provocation test was defined as documented AF on electrocardiogram during the procedure. There were 31 patients (8%) with paroxysmal AF during the test. Of these, 11 (35%) required antiarrhythmic drugs, but none received electrical cardioversion. All of them recovered sinus rhythm within 48 h. At procedure, paroxysmal AF occurred mostly during provocation for the right coronary artery (RCA) rather than for the left coronary artery (LCA) (90 vs. 10%). Multivariate logistic regression analysis demonstrated that a history of paroxysmal AF (OR 4.38 CI 1.42–13.51, p  = 0.01) and body mass index (OR 0.88 CI 0.78–0.99, p  = 0.03) were independent predictors for occurrence of paroxysmal AF during intracoronary ACh provocation test. In conclusions, paroxysmal AF mostly occurs during ACh provocation test for the RCA, especially in patients with a history of paroxysmal AF and lower body mass index. It may be better to initially administer intracoronary ACh in the LCA when the provocation test is performed.

Rh-rich and Ir-poor erlichmanite-laurite OsS2-RuS2 solid solutions have been discovered at placers in Haraigawa, Misato-machi, Kumamoto, Japan. Microprobe analysis was performed to identify solid solutions containing few sub-components other than Rh. Approximately 10 at.% Rh was found to be present in the solid-solution samples. Structural refinement was performed using four natural samples: Os0.32Ru0.61Rh0.07S2, Os0.49Ru0.43Rh0.08S2, Os0.58Ru0.33Rh0.08S2 and Os0.81Ru0.09Rh0.10S2. The unit-cell parameters for the solid solutions containing Rh from Haraigawa varied from 5.61826(6) to 5.63142(8) Å. The (Os, Ru, Rh)-S distances in the Os1-x-yRuxRhyS2 system were almost constant with a small variation of 0.001 Å. Conversely, the S-S distances varied significantly, with variations approaching 0.1 Å. Rh substitution of Os rather than Ru had a larger impact on the crystal structure. The atomic displacement ellipsoid of both cations and anions was almost spherical, and no elongation along the M-S and S-S bond directions was observed. The bulk Debye temperatures were estimated from the Debye-Waller factor for the sulfide site. The bulk Debye temperatures of pure OsS2 and RuS2 were 688 K and 661 K, respectively, which suggests that the melting point of erlichmanite is higher than that of laurite. The high Debye temperature of OsS2 is inconsistent with the crystallisation of laurite prior to erlichmanite from the primitive magma, which suggests that fS2, rather than temperature, is the main cause of the known crystallisation order. The presence of several percent Rh has a significant effect on the thermal stability of OsS2 and lowers the melting point of the erlichmanite solid solution compared to that of the laurite solid solution.

Stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) has been shown to enhance endothelial healing after spontaneous or iatrogenic arterial disruption. Granulocyte colony-stimulating factor treatment might attenuate endothelial dysfunction after sirolimus-eluting stent (SES) implantation that may be associated with adverse cardiac events during follow-up. This prospective, double-blind, randomized, placebo-controlled study investigated whether G-CSF improved endothelial dysfunction after SES implantation. One hundred patients who underwent SES implantation were randomly assigned to the G-CSF (n = 50) or the placebo group (n = 50). They received daily subcutaneous injection of 300 μg G-CSF or saline for 5 days. Endothelial function was estimated by measuring the coronary vasoreactivity in the segments 15 mm proximal and distal to SES in response to intracoronary infusion of acetylcholine (10−8 and 10−7 mol/L) at 9-month follow-up. Follow-up angiography was performed in 41 G-CSF patients (82%) and 46 placebo patients (92%) (P = .14). Changes in coronary diameter in response to acetylcholine infusion in the proximal segment were not significantly different between the 2 groups. However, vasoconstriction in the distal segment in response to 10−8 mol/L (−3.9% ± 6.4% vs −7.0% ± 8.1%, P < .05) and 10−7 mol/L (−8.8% ± 11.0% vs −15.2% ± 7.6%, P < .01) acetylcholine infusion was attenuated in the G-CSF group. Endothelium-independent vasodilatation after nitrate infusion did not differ between the 2 groups. Granulocyte colony-stimulating factor attenuates endothelial dysfunction after SES implantation.

Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.

Intracoronary acetylcholine (ACh) provocation test is useful to diagnose vasospastic angina. Although outpatient coronary angiography has been widely performed in current clinical settings, the feasibility and safety of ACh provocation test in outpatient services are unclear. A total of 323 patients, who electively underwent ACh provocation test in hospitalization and outpatient services, were included. Coronary angiography was performed after insertion of a temporary pacing electrode in the right ventricle. The positive diagnosis of intracoronary ACh provocation test was defined as total or subtotal coronary artery narrowing accompanied by chest pain and/or ischemic electrocardiographic changes. Cardiac complications defined as composite of death, ventricular fibrillation or sustained ventricular tachycardia, myocardial infarction, cardiogenic shock, and cardiac tamponade, were evaluated. There were 201 patients (62%) in the hospitalization group and 122 patients (38%) in the outpatient group. The incidence of positive ACh provocation test was similar between the 2 groups (47 vs. 54%, p  = 0.21). Coronary angiography in the outpatient group was performed through the radial artery, mostly (98%) with a 4 F sheath. Venous access site was not significantly different between the 2 groups, and the sheath size was 5 F in all cases. There were 2 cases (1.0%) of cardiac complications in the hospitalization group, whereas 1 case (0.8%), which led to unexpected hospitalization, occurred in the outpatient group. In conclusion, intracoronary ACh provocation test for the diagnosis of vasospastic angina in outpatient services was feasible and safe in selected patients.

In Japan, a lower maintenance dose of ticlopidine is used than in the United States and Europe. Therefore a lower maintenance dose of clopidogrel may also be considered appropriate in Japanese patients. The present randomized pilot study evaluated the efficacy and safety of 50 mg clopidogrel in Japanese patients who underwent drug-eluting stent (DES) implantation. A total of 200 patients with 277 lesions who underwent intravascular ultrasound-guided DES implantation were enrolled. The subjects were allocated to the 50- or 75-mg clopidogrel group. All patients received 100 mg aspirin daily before the procedure, and this continued indefinitely. The duration of clinical follow-up was 21.8 ± 5.7 months in the 75-mg group and 21.9 ± 6.1 months in the 50-mg group ( P = 0.96). During follow-up, no cardiac death, myocardial infarction, or stent thrombosis was observed in either group. Side effects of clopidogrel were observed in 4 patients (4.0 %) in the 75-mg group and in 4 patients (4.0 %) in the 50-mg group. Following this randomized pilot study, it may be justified to perform a large-scale randomized study comparing 50- and 75-mg dosing of clopidogrel in Japanese patients undergoing coronary stent implantation.

We determined the associations of follow-up blood pressure (BP) after stroke as a time-dependent covariate with the risk of subsequent ischemic stroke, as well as those of BP levels with the difference in the impact of long-term clopidogrel or aspirin monotherapy versus additional cilostazol medication on secondary stroke prevention. In a sub-analysis of a randomized controlled trial (CSPS.com), patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol with aspirin or clopidogrel. The percent changes, differences, and raw values of follow-up BP were examined. The primary efficacy outcome was the first recurrence of ischemic stroke. In a total of 1657 patients (69.5 ± 9.3 years, female 29.1%) with median 1.5-year follow-up, ischemic stroke recurred in 74 patients. The adjusted hazard ratio for ischemic stroke of a 10% systolic BP (SBP) increase from baseline was 1.19 (95% CI 1.03–1.36), that of a 10 mmHg SBP increase was 1.14 (1.03–1.28), and that of SBP as the raw value with the baseline SBP as a fixed (time-independent) covariate was 1.14 (1.00–1.31). Such significant associations were not observed in diastolic BP-derived variables. The estimated adjusted hazard ratio curves for the outcome showed the benefit of dual therapy over a wide SBP range between ≈120 and ≈165 mmHg uniformly. Lower long-term SBP levels after ischemic stroke were associated with a lower risk of subsequent ischemic events. The efficacy of dual antiplatelet therapy including cilostazol for secondary stroke prevention was evident over a wide SBP range.