Biomimetic Construction of a syn-2,7-Dimethyloxepane Ring via 7-Endo Cyclization.

syn-2,7-Dimethyloxepane is a unique structure observed in natural ladder-shaped polycyclic ethers (LSPs), such as Caribbean ciguatoxins, gymnocin-B, and brevisulcenal-F that exhibit potent biological activities. Thus, the successful construction of this seven-membered ring is desirable, but its ring strain and the 1,3-repulsion between its two methyl groups makes this process difficult. Herein, we prepared syn-2,7-dimethyloxepanes via 7-endo cyclizations of vinyl epoxides that break Baldwin's rules. Such a biomimetic approach to syn-2,7-dimethyloxepanes has not yet been reported; however, we achieved this challenging cyclization with the aid of a cis-olefin tether and an unsubstituted vinyl group. The NO-ring fragment of gymnocin-B was also prepared from one of these 7-endo cyclized products, demonstrating the potential application of this strategy in constructing bioactive LSPs.

Discharge disposition and 1-year readmission in acute-phase hospitalized patients with heart failure: a retrospective observational multi-center study.

Patients hospitalized for acute heart failure (HF) tend to experience declines in physical function and activities of daily living (ADL) due to bed rest and restricted mobilization. This could result in some patients being transferred to rehabilitation hospitals. This study aims to examine the relationship between discharge disposition and 1-year readmission and mortality rates in HF patients. Nine hundred fifty six consecutive HF patients who were hospitalized for acute decompensated HF and underwent rehabilitation were divided into two groups: home (returned home) or transfer (transferred to rehabilitative or long-term care hospital units due to decline in physical function and/or ADL) groups. The primary and secondary outcomes were 1-year readmission and mortality rates after discharge, respectively. Of the 956 patients, 8.6% (n = 82) were transferred to rehabilitative or long-term care hospital units. Over a 1-year follow-up period, all-cause and HF readmission rates were 50.1% (n = 479) and 27.2% (n = 260), respectively. The transfer group had significantly lower readmission rates compared to home group after adjusting for the pre-existing risk factors (hazard ratio for all-cause and HF readmission: 0.600 and 0.552, 95% CI 0.401-0.897 and 0.314-0.969; P = 0.013 and P = 0.038, respectively). There was no significant relationship between discharge disposition and all-cause mortality rate. Low ADL defined as Barthel index < 60 points was identified as a predictor of all-cause and HF readmission among the home group (odds ratio for all-cause and HF readmission rates: 2.156 and 1.847, 95% CI 1.026-4.531 and 1.036-2.931; P = 0.043 and P = 0.037, respectively). This multi-center study demonstrated that HF patients transferred to rehabilitative or long-term care hospital units after an acute hospitalization had a significantly decreased 1-year all-cause and HF readmission rates compared to patients who returned to their home. These findings may help in selecting a discharge disposition for older HF patients with ADL decline.

Investigation of the sensitization rate for gibberellin-regulated protein in patients with Japanese cedar pollinosis.

BACKGROUND: Pollen-food allergy syndrome (PFAS) usually manifests as an itching sensation in the mouth and throat immediately after eating fresh fruits and vegetables. However, some patients with PFAS experience systemic symptoms including anaphylaxis. In Europe, cypress gibberellin-regulated protein (GRP) has been noted to cause allergenicity and exhibit cross-reactivity with peach GRP. Japanese cedar (Cryptomeria japonica), classified in the cypress family, is the primary causative substance among all environmental allergens in Japan. However, studies on the prevalence of GRP sensitization in patients with cedar pollinosis are lacking. OBJECTIVE: This study examined the prevalence of GRP sensitization in patients with Japanese cedar pollinosis. METHODS: We enrolled 52 patients who had requested sublingual immunotherapy treatment with mild-to-severe rhinitis during spring, and had a JCP-specific immunoglobulin E (IgE) levels of >0.7 UA/mL. Peach GRP was purified using affinity chromatography with a monoclonal antibody column. Specific IgE levels to peach GRP were measured using an enzyme-linked immunosorbent assay. Samples exhibiting absorbance at 450 nm of over mean plus three standard deviations of the negative control value were defined as positive. Sera from three patients with severe peach allergy were used as positive controls. RESULTS: Eleven sera from 52 patients with JCP-induced allergic rhinitis were positive for peach GRP. CONCLUSION: Twenty percent of patients with cedar pollinosis were sensitized to peach GRP. Well-powered studies are needed to clarify whether these patients are at an increased risk for systemic symptoms or whether they primarily demonstrate only localized symptoms.

p-Methoxy- and 2,4-Dimethoxybenzyl N-Acetylcarbamate Potassium Salts: Versatile Reagents for N-Alkylacetamide and p-Methoxy- and 2,4-Dimethoxybenzyl Carbamates.

The acetamide moiety is a general functional group present in many natural and pharmaceutical products. Herein, we report two new reagents, p-methoxybenzyl N-acetylcarbamate potassium salt (PM-BENAC-K) and 2,4-dimethoxybenzyl N-acetylcarbamate potassium salt (2,4-DM-BENAC-K), which are refined versions of the benzyl N-acetylcarbamate potassium salt (BENAC-K). These compounds, which we reported as simple equivalents of N-acetamide nucleophiles, are stable and easy-to-handle powders that react with a variety of alkyl halides and sulfonates to afford substituted products in good yields. The products were transformed into N-alkylacetamides after p-methoxybenzyloxycarbonyl (Moz) or 2,4-dimethoxybenzyloxycarbonyl (Dmoz) cleavage under mild acidic conditions. The acetyl groups in the substituted products of PM- and 2,4-DM-BENAC-Ks were removed using K2CO3 in methanol to afford Moz- and Dmoz-protected amines, respectively. Hence, the new BENAC-Ks acted as versatile equivalents of both N-acetamide and Moz/Dmoz-protected nitrogen nucleophiles and can be used in synthetic studies of natural and pharmaceutical products.

Development of New Synthetic Methods Using Oxiranyl Anions and Application in the Syntheses of Polycyclic Ether Marine Natural Products.

This review reports on the development of new synthetic methods using oxiranyl anions and their application to the synthesis of polycyclic ether marine natural products. Novel iterative and convergent methods for large, complex polycyclic ether structures have been devised. In these, the reactions of sulfonyl-stabilized oxiranyl anions were employed to construct trans-fused polyether ring systems, along with 6-endo cyclization and ring expansion reactions. Total syntheses of polycyclic ether marine toxins, viz. hemibrevetoxin B, gambierol, and gymnocin-A, were achieved based on the oxiranyl anion strategy developed.

Synthesis of the KLMN Fragment of Gymnocin-A from the FGH Fragment.

An improved route for the synthesis of the KLMN fragment of gymnocin-A was developed through the oxiranyl anion coupling of the FGH fragment with a chiral C3 epoxy sulfone, followed by 6-endo cyclization. This straightforward approach reduced the number of synthetic steps by 14 compared with a previous route using alternative building blocks.

CAr-O Rotamers in 3,3'-Disubstituted BINOL Esters.

Rotamers around the CAr-O bond were disclosed in 3,3'-disubstituted BINOL esters by NMR spectroscopy. A bulky R1 group increased the rotational barrier. The pivalate showed two rotamers at 2 °C, and broad signals were observed close to room temperature when R2 = Ph. The highest rotational barrier was recorded for the (tetracyanocyclopentadienyl)carboxylate, and C-O rotamers were present at room temperature. DFT calculations indicated the presence of repulsion between R1 and R2 during rotation of the CAr-O bond.

Identification of a pheromone that increases anxiety in rats.

Chemical communication plays an important role in the social lives of various mammalian species. Some of these chemicals are called pheromones. Rats release a specific odor into the air when stressed. This stress-related odor increases the anxiety levels of other rats; therefore, it is possible that the anxiety-causing molecules are present in the stress-related odorants. Here, we have tried to identify the responsible molecules by using the acoustic startle reflex as a bioassay system to detect anxiogenic activity. After successive fractionation of the stress-related odor, we detected 4-methylpentanal and hexanal in the final fraction that still possessed anxiogenic properties. Using synthetic molecules, we found that minute amounts of the binary mixture, but not either molecule separately, increased anxiety in rats. Furthermore, we determined that the mixture increased a specific type of anxiety and evoked anxiety-related behavioral responses in an experimental model that was different from the acoustic startle reflex. Analyses of neural mechanisms proposed that the neural circuit related to anxiety was only activated when the two molecules were simultaneously perceived by two olfactory systems. We concluded that the mixture is a pheromone that increases anxiety in rats. To our knowledge, this is the first study identifying a rat pheromone. Our results could aid further research on rat pheromones, which would enhance our understanding of chemical communication in mammals.

Three infants with rotavirus gastroenteritis complicated by severe gastrointestinal bleeding.

Rotavirus gastroenteritis causes substantial morbidity and mortality worldwide in children. We report three infants with rotavirus gastroenteritis complicated by various severity of gastrointestinal bleeding. Two patients (cases 1 and 2) recovered completely without any specific treatments. One patient (case 3) died despite extensive treatments including a red blood cell transfusion and endoscopic hemostatic therapy. Rotavirus genotypes G1P[8] and G9P[8] were detected in cases 2 and 3, respectively. Rotavirus antigenemia levels were not high at the onset of melena, suggesting that systemic rotaviral infection does not play an important role in causing melena.

Social buffering ameliorates conditioned fear responses in female rats.

The stress experienced by an animal is ameliorated when the animal is exposed to distressing stimuli along with a conspecific animal(s). This is known as social buffering. Previously, we found that the presence of an unfamiliar male rat induced social buffering and ameliorated conditioned fear responses of a male rat subjected to an auditory conditioned stimulus (CS). However, because our knowledge of social buffering is highly biased towards findings in male subjects, analyses using female subjects are crucial for comprehensively understanding the social buffering phenomenon. In the present studies, we assessed social buffering of conditioned fear responses in female rats. We found that the estrus cycle did not affect the intensity of the rats' fear responses to the CS or their degree of vigilance due to the presence of a conspecific animal. Based on these findings, we then assessed whether social buffering ameliorated conditioned fear responses in female rats without taking into account their estrus cycles. When fear conditioned female rats were exposed to the CS without the presence of a conspecific, they exhibited behavioral responses, including freezing, and elevated corticosterone levels. By contrast, the presence of an unfamiliar female rat suppressed these responses. Based on these findings, we conclude that social buffering can ameliorate conditioned fear responses in female rats.

The strain of an accompanying conspecific affects the efficacy of social buffering in male rats.

Social buffering is a phenomenon in which stress in an animal is ameliorated when the subject is accompanied by a conspecific animal(s) during exposure to distressing stimuli. We previously reported that in male Wistar rats, the presence of another Wistar rat mitigates conditioned fear responses to an auditory conditioned stimulus (CS). Subsequent analyses revealed several characteristics of this social buffering of conditioned fear responses. However, information regarding the specificity of accompanying conspecifics is still limited. In the present study, we assessed whether rats of other strains could induce social buffering in Wistar rats. When a fear-conditioned Wistar subject was re-exposed to the CS alone, we observed increased freezing and decreased investigation and walking, as well as elevated corticosterone levels. The presence of a Wistar, Sprague-Dawley, or Long-Evans rat blocked these responses, suggesting that social buffering was induced by these strains of rats. In contrast, a Fischer 344 rat did not induce social buffering in the Wistar subject. We further found that an inbred Lewis rat induced social buffering whereas a Brown Norway rat, a strain that has been established independently from Wistar rats, did not. These results suggest that the difference in origin, rather than the inbred or outbred status of the associate rat, seemed to account for the lack of social buffering induced by the F344 rats. Based on these findings, we conclude that strains of an accompanying conspecific can affect the efficacy of social buffering in rats.

Total Synthesis of Brevisamide Using an Oxiranyl Anion Strategy.

A total synthesis of brevisamide, a marine monocyclic ether amide isolated from the dinoflagellate Karenia brevis, has been achieved in 18 steps starting from 4-(benzyloxy)butanol. The synthesis involves oxiranyl anion coupling between an epoxy sulfone and a triflate, intramolecular etherification of a hydroxy-bromoketone, diastereoselective introduction of the axial methyl group by hydroxyl-directed hydrogenation of an exocyclic olefin, and installation of an acetamide side chain by nucleophilic substitution of an N-acetyl carbamate. The dienal side chain is assembled using a Horner-Wadsworth-Emmons reaction to complete the synthesis.

Acceleration of Acid-Catalyzed Hydrolysis in a Biphasic System by Sodium Tetracyanocyclopentadienides.

The hydrolysis of tert-butyldimethylsilyl L-menthyl ether (3) in a CH2Cl2-1 M HCl biphasic solvent system was accelerated by the addition of sodium tetracyanocyclopentadienides 1. Particularly, the reaction rate was enhanced using sodium salt 1a-c with a lipophilic substituent on the cyclopentadienide ring. From the results obtained by a triphasic experiment, hydrolysis proceeds via the formation of hydronium ion 2 in the aqueous phase by ion exchange, followed by the transfer of 2 to the CH2Cl2 phase.

[Satisfactory Sedation for a Morbidly Obese Woman by Dexmedetomidine Dosed on the Basis of Total Body Weight under Spinal Anesthesia ; A Case Report].

A 45-year-old morbidly obese woman (body mass index 51.9) was scheduled for right knee arthroscopic synovectomy. We selected spinal anesthesia in order to avoid difficult ventilation or intubation during anes- thetic induction of general anesthesia. As she strongly requested unawareness during operation, we decided to sedate her with dexmedetomidine(DEX), a sedative drug which has little possibility to cause upper airway obstruction and respiratory depression. Dose of DEX was determined based on total body weight (TBW) instead of ideal body weight To achieve adequate sedation, DEX was titrated by monitoring Ramsay sedation score (RSS), and was discontinued 10 minutes before the end of operation. She was well sedated dur- ing the operation but developed minimal upper airway obstruction and respiratory depression. She showed a good recovery profile when discharged from the oper- ating room. She was very satisfied with the anesthetic management The similar patient's satisfaction was also obtained at the opposite knee joint operation per- formed using the same anesthetic management Conse- quently, DEX infusion based on TBW appears to be suitable to sedate a morbidly obese patient.

Total Synthesis of Gymnocin-A.

A convergent total synthesis of cytotoxic marine natural polycyclic ether, gymnocin-A (1), is described. The synthesis features three iterations of an oxiranyl anion strategy, involving base-mediated cycloetherification, ring expansion, and reductive etherification, for the construction of the FGH fragment and for its coupling with the ABC and KLMN fragments.

The emission of stress-induced 22-kHz calls in female rats is independent of testosterone levels.

Although emission of ultrasonic calls in rats induced by stress, referred to as "22-kHz calls," is dependent on circulating testosterone levels in males, it is still unknown whether the same testosterone-based regulation is applicable to female rats. In this study, we investigated the sex difference in the emission of air-puff-induced 22-kHz calls in rats on the basis of the hypothesis that female rats would emit fewer 22-kHz calls, and assessed whether male-like circulating testosterone levels can also influence the emission of 22-kHz calls in females. The experimental results showed that female rats emit significantly fewer 22-kHz calls than male rats. However, male-like circulating testosterone levels have little effect on the emission of 22-kHz calls in females. Hence, it is suggested that there is a sex difference in stress-induced 22-kHz calls in rats and, in contrast to male rats, the emission of 22-kHz calls in female rats may be independent of circulating testosterone levels, as tested in response to air-puff stimulation.

Synthesis of alkynes from vinyl triflates using tetrabutylammonium fluoride.

A convenient method for the preparation of alkynes and alkynyl esters from ketones and ß-keto esters is described which involves the formation of vinyl triflates, followed by elimination with tetrabutylammonium fluoride trihydrate, to give alkynes. Unlike established elimination methods, the method requires neither a strong base nor anhydrous conditions.