Exploring Downhill Bifurcations in [3,3]-Sigmatropic Rearrangement by Finding Transitions from an Uphill Bifurcation to a Downhill Bifurcation.

Downhill bifurcation is a phenomenon in which an ensemble of trajectories passing through a transition state (TS), called an ambimodal TS, bifurcates into multiple products. Finding downhill bifurcations for unreported pairs of chemical transformations is essential, because they affect reaction selectivity. Marx et al. reported that perturbations such as applying mechanical stress or changing a substituent cause a transition from an uphill bifurcation to a downhill bifurcation in the ring-opening reaction of cyclopropane derivatives (ChemPhysChem, 2018, 19, 837-847). Investigating the occurrence of this phenomenon in other reactions, especially in pericyclic reactions, is interesting for understanding and controlling the reaction selectivity considering downhill bifurcations. In this study, we proposed a method for finding perturbation-induced downhill bifurcations and applied it to three pericyclic reactions. The transition from an uphill bifurcation to a downhill bifurcation occurred in two of the three pericyclic reactions, one of which was previously unreported. Interestingly, the occurrence of a downhill bifurcation by a perturbation depended on the directions of the intrinsic reaction coordinate paths of the two TSs when they emerged from the reactant minimum. Our method can be applied in mechanistic studies to avoid the risk of overlooking downhill bifurcations.

Catastrophic antiphospholipid syndrome with Epstein-Barr virus-associated hemophagocytosis: A clinicopathological conference.

Catastrophic antiphospholipid syndrome (CAPS) is a severe variant of antiphospholipid syndrome associated with multiorgan thrombosis in a short term. We present the case of a 14-year-old immunocompetent girl who developed renal, intestinal, and pulmonary infarction; thrombocytopenia; and hemolytic anemia within 1 week. She was diagnosed with thrombotic microangiopathy. Hence, plasma exchange and corticosteroid therapy were initiated, which improved thrombocytopenia. However, the patient's platelet count decreased. Her general condition gradually worsened with eventual death. An autopsy revealed multiple infarctions in the kidneys bilaterally, jejunum, ileum, and pulmonary parenchyma. Microthrombi were not detected. Massive hemophagocytosis was observed in the splenic pulp, lymph nodes, and bone marrow. Several Epstein-Barr viruses (EBVs)-encoded small ribonucleic acid (RNA)-positive lymphocytes were also found in the bone marrow. The presence of antibodies to both viral capsid antigen-immunoglobulin G and EBV nuclear antigen indicated past infection. Antiphospholipid antibody was positive after her death. The patient was finally diagnosed with CAPS and EBV-associated hemophagocytosis, possibly due to EBV reactivation. Establishing a clinical diagnosis of CAPS was relatively difficult because two different causes of thrombocytopenia, CAPS and hemophagocytosis, led to a difficulty in understanding this case's pathogenesis.

An in vitro system for experimentally induced cryptorchidism.

Cryptorchidism is one of the most common abnormalities of male sexual development, and is characterized by the failure of the testis to descend into the scrotum. Despite extensive studies of cryptorchidism over the past century, the mechanisms for temperature-induced germ-cell loss are not well understood. All of the main cell types in the testis are believed to be affected by the elevated testis temperature induced by cryptorchidism. The cooler temperature in the special environment of the scrotum is required for maintaining optional conditions for normal spermatogenesis. Many studies reported that experimentally induced cryptorchidism caused germ cell apoptosis and suppressed spermatogenesis. However, other factors including hormones must also be examined for cryptorchidism. To explore the mechanism for cryptorchidism, in vitro cultures of testes have been used, but complete spermatogenesis using in vitro methods was not accomplished until 2011. In 2011, Sato et al. (Nature, 471, 504-507) reported the in vitro production of functional sperm in cultured neonatal mouse testes. Using this in vitro system, for the first time, we report that spermatogenesis was abrogated at 37 °C, in accordance with in vivo surgery-mediated cryptorchidism, while spermatogenesis proceeded at 34 °C in cultured testes. This result clearly showed that temperature is the sole determinant of cryptorchidism. Moreover, we found that spermatogenesis was arrested before early spermatocytes at 37 °C. In conclusion, using our in vitro system, we have demonstrated that (1) temperature is the determining factor for cryptorchidism, and (2) higher temperature (37 °C) suppresses DNA synthesis in spermatogenesis.

Kinetic Analysis of a Reaction Path Network Including Ambimodal Transition States: A Case Study of an Intramolecular Diels-Alder Reaction.

This study proposes a methodology for the kinetic analysis of a reaction path network including ambimodal transition states (TSs), through which an ensemble of trajectories bifurcates to multiple minima in a phenomenon called dynamical bifurcation. The proposed methodology consists of three techniques: an automated reaction path search to construct a reaction path network including ambimodal TSs, an ab initio molecular dynamics simulation to evaluate the branching ratio, and the definition of rate constants incorporating this ratio. Applying the procedure to a Diels-Alder reaction, it was found that the inclusion of dynamical bifurcations is necessary to explain the experimental reaction yield of a byproduct. In addition, it was verified that the products take 1013 s to reach thermal equilibrium and that the experimental selectivity is determined by the dynamical bifurcations.

Hemophilic pseudotumor of the maxillary sinus in an inhibitor-positive patient with hemophilia A receiving emicizumab: a case report.

A 14-year-old inhibitor-positive male patient with severe hemophilia A and severe psychomotor disability was admitted due to left buccal swelling and impaired downward movement of the left eye. He had been on noninvasive positive-pressure ventilation (NPPV) through a nasal mask for upper airway obstruction. The patient began to have repeated epistaxis 16 months after initiation of treatment with 6 mg/kg Q4W of emicizumab, and was thus administered a bypassing agent. Left buccal swelling and impaired downward movement of the left eye appeared during the subsequent month. Imaging examination revealed a mass in the left maxillary sinus and bone destruction. Endoscopic tumor resection and tracheostomy were performed using recombinant activated factor VII. NPPV was discontinued thereafter. Pathological examination revealed that the mass was a hemophilic pseudotumor (HP). After discharge the emicizumab-regimen dose was changed to 3 mg/kg, Q2W to increase serum emicizumab levels. No recurrent HP or bleeding requiring treatment was observed. Pressure applied to the damaged nasal mucosa by NPPV was suspected as the main cause of HP development. If a mass is observed in a patient with hemophilia, HP should be considered as a possible diagnosis even if the patient is receiving emicizumab.

Primary and recurrent serous borderline tumors during pregnancy: a case report and literature review.

The diagnosis and management of borderline ovarian tumors during pregnancy are still not standardized, because these tumors are rarely encountered. We report the case of a 27-year-old pregnant woman who presented with an ovarian mass in her first trimester. Magnetic resonance imaging revealed a multilocular cystic component with papillary lesions in the background of endometriosis, suggesting a seromucinous borderline tumor or ovarian cancer. A right salpingo-oophorectomy and partial omentectomy were performed at 7 weeks of gestation. Pathological examination demonstrated a serous borderline tumor. The subsequent pregnancy course was uneventful, and she gave birth to a healthy baby at 39 weeks of gestation. She wanted to retain fertility, and close follow-up was performed. Four years later, she became pregnant, and a lesion suggesting recurrence in the left ovary was detected. An abdominal left ovarian cystectomy was performed at 13 weeks of gestation, which demonstrated recurrence of the serous borderline tumor. She gave birth to a healthy baby at 39 weeks of gestation. Two months after delivery, she underwent total abdominal hysterectomy with left salpingo-oophorectomy, which revealed no malignant findings. We also reviewed 10 reports that included 58 cases of borderline ovarian tumors diagnosed during pregnancy. The borderline ovarian tumors diagnosed during pregnancy exhibited different characteristics according to each subtype, suggesting the importance of diagnosing borderline ovarian tumor subtypes preoperatively.

[Acquired hemophilia A with reappearance of inhibitor 10 years after the completion of immunosuppressive therapy].

Acquired hemophilia A (AHA) is a disease that causes severe bleeding with the appearance of an inhibitor (INH) against blood coagulation factor VIII (FVIII). The prevalence of this condition is low; it occurs in only one in one to four million people per year; however, the number of diagnosed cases has increased in recent years owing to the greater awareness of the disease. It is noteworthy that this is a hemorrhagic disease that suddenly develops in the elderly. AHA treatment is divided into hemostatic treatment for bleeding and immunosuppressive therapy (IST) for removing FVIII-INH. As long as FVIII-INH remains, there is a risk of fatal bleeding; therefore, it is desirable to start IST soon after diagnosis. However, the use of immunosuppressive drugs for the elderly is often challenging due to concerns about adverse events, such as infectious diseases that have a considerable impact on prognosis. Ten years after the end of IST, we managed the case of a patient with AHA who had a relapse of FVIII-INH at the age of 84 years. In this case, relapse was detected early when there was no bleeding symptom, and remission was rapidly achieved with a small amount of IST without any adverse effects. There are few reports on AHA relapse; we believe that the present report will contribute meaningfully to the literature on this subject and would be useful when considering the long-term management of AHA.

AFIR explorations of transition states of extended unsaturated systems: automatic location of ambimodal transition states.

Paths of Diels-Alder reactions between 2-vinylfuran and 3-methoxycarbonylcyclopentadienone were systematically explored by the multicomponent version of the artificial force induced reaction (MC-AFIR) method. In this reaction, the dynamical bifurcation in which a single transition state (TS) relates to two different products has been reported to occur [J. B. Thomas, et al., J. Am. Chem. Soc., 2008, 130, 14544-14555]. In this paper, based on the MC-AFIR method, we propose a procedure to systematically explore so called ambimodal TSs through which the dynamical bifurcation occurs. The present procedure finds candidates of TSs that may cause the dynamical bifurcation from the logs of an automated reaction path search by the MC-AFIR method, without any additional quantum chemical calculations. For this reaction, the MC-AFIR search found 125 unique TSs automatically. Among the 125 TSs, 19 were suggested as candidates, and finally, six including the one reported in the literature were confirmed to cause the dynamical bifurcation. The present procedure would be promising to find TSs involved in the dynamical bifurcation automatically.

A pediatric case with parvovirus B19-associated uveitis without autoantibody formation.

Acute parvovirus B19 (B19) infection is often accompanied by autoantibody formation, including antinuclear antibodies and rheumatoid factor, and the symptoms of the infection are similar to those of several autoimmune diseases. Uveitis is a representative manifestation of autoimmune diseases and is rarely caused by B19. Autoantibody formation was confirmed in 2 previously reported cases with B19-associated uveitis. However, whether B19-associated uveitis is caused by the direct invasion of the virus or the induction of autoimmunity remains unclear. We herein report a pediatric case with B19-associated uveitis without autoantibody formation. We speculated that B19 might have directly invaded the eye in this patient because of the development of uveitis without antibody formation and the negative results for anti-B19-specific antibodies in the serum at the onset of the disease. Although the mechanism of invasion is unknown, B19 may have a high affinity for tissue in the eye.

Expectant management for abdominal pregnancy.

This is the first English language report describing the expectant management for abdominal pregnancy. The patient was a 31-year-old multiparous woman who was transferred to our hospital on suspicion of ectopic pregnancy. Her serum human chorionic gonadotropin was positive, and a poorly-vascularized mass measuring about 4 cm was visualized in the Douglas pouch by transvaginal ultrasonography, as well as by pelvic magnetic resonance imaging. Because the bilateral adnexa were apparently intact, she was diagnosed with abdominal pregnancy, and expectant management was commenced. Unexpectedly, the mass remained in situ for nearly 3 years after her serum human chorionic gonadotropin tested negative. Laparoscopic removal of the mass was finally required because of persistent defecation pain. This case illustrates that some abdominal pregnancies can be managed expectantly, as is the case with tubal pregnancies. During the expectant management, however, it should be considered that the abdominal pregnancy mass may persist for a longer period and cause moderate symptoms necessitating surgical removal.

Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Sorafenib has various adverse events that can cause treatment discontinuation or dose reduction. The aim of this study was to compare the safety profile between renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) patients receiving sorafenib under real-life practice conditions. Furthermore, we investigated the relationship between sorafenib exposure and clinical outcomes. METHODS: A total of 91 Japanese cancer patients (RCC, n = 21; HCC, n = 70) treated with sorafenib were enrolled. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0. Single blood samples were collected at each clinic visit and serum sorafenib concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The incidence of adverse events was analyzed according to cancer type and sorafenib concentration. RESULTS: Hand-foot skin reaction (HFSR) was the most common adverse event among RCC (76 %) and HCC (66 %) patients. Elevations in hepatic transaminases and pancreatic amylase developed more frequently in patients with RCC than in those with HCC (p < 0.05), while hyperbilirubinemia and thrombocytopenia were observed more often in HCC patients than in RCC patients (p < 0.05). Pharmacokinetic data were available from 52 patients (RCC, n = 16; HCC, n = 36). HCC patients showed significantly higher dose-normalized concentrations than RCC patients (p = 0.0184). Sorafenib concentrations were significantly greater in patients with grade ≥2 HFSR and hypertension than in those not experiencing the adverse events (p = 0.0045 and 0.0453, respectively). Furthermore, receiver operating characteristic curves revealed optimal cutoff concentrations of sorafenib to predict grade ≥2 HFSR (5.78 µg/mL) and hypertension (4.78 µg/mL). In addition, a trend of prolonged overall survival was observed in HCC patients who achieved a maximal sorafenib concentration of ≥4.78 µg/mL during treatment compared with those who did not achieve the threshold concentration (12.0 vs. 6.5 months; log-rank p = 0.0824). CONCLUSIONS: The results of this study suggest that the safety and pharmacokinetic profiles of sorafenib differ between Japanese cancer patients with RCC and HCC. Furthermore, the serum sorafenib concentration could be used as a guide to avoiding the development of severe HFSR while allowing prediction of the incidence of grade ≥2 hypertension in patients with RCC and HCC, and may potentially be related to the clinical efficacy of sorafenib for HCC.