Catalytic 1,1-Cyanoalkylation of Electron-Deficient Olefins.

A catalytic 1,1-dicarbofunctionalization of electron-deficient olefins was effected on the basis of the three-component coupling reactions involving olefins bearing vicinal electron-withdrawing groups, potassium cyanide, and an alkyl halide, which afforded geminally cyanoalkylated products in high yields via conjugate cyanation, 1,2-proton transfer, and enolate alkylation. The use of suitable chiral phase-transfer catalysts enabled asymmetric induction in this transformation.

Use of amlodipine in the treatment of cats with systemic hypertension in Japan.

An increase in systemic blood pressure causes bleeding and ischemia owing to peripheral vascular breakdown, leading to various forms of organ damage. The brain, eyes, kidneys, and cardiovascular system are known target organs for hypertension. To our knowledge, no reports in Japan describe, in detail, the types of antihypertensive drugs used to treat hypertension in cats or its underlying causes. Therefore, we aimed to investigate the use of antihypertensive drugs in domestic cats with hypertension in Japan, the causes of hypertension, and the vital prognosis of these patients. In the present survey, we found that amlodipine was used alone (60/80 cats) or concomitantly (20/80 cats) in all cat patients with hypertension in Japan. We also determined that blood pressure measurements were not yet routinely performed on cats at veterinary clinics in Japan. Furthermore, we have new information suggesting that amlodipine administration in cats with hypertension, which lowers systolic arterial pressure levels to within the normal range (<140 mmHg), may have a negative impact on their survival. Routine blood pressure measurements for cats during their regular health checkups can help identify hypertension, and proper interpretation of blood pressure readings can facilitate suitable treatment measures.

Comparative pharmacokinetics of tyrosine kinase inhibitor, lapatinib, in dogs and cats following single oral administration.

Lapatinib is an orally administered tyrosine kinase inhibitor used to treat human epidermal growth factor receptor 2 (HER2) -overexpressing breast cancers in humans. Recently, the potential of lapatinib treatment against canine urothelial carcinoma or feline mammary tumor was investigated. However, the pharmacokinetic studies of lapatinib in dogs and cats are not well-defined. In the present study, the pharmacokinetic characteristics of lapatinib in both cats and dogs after a single oral administration at a dose of 25 mg/kg were compared with each other. Lapatinib was administered orally to four female laboratory cats and four female beagle dogs. Blood samples were collected over time, and the plasma lapatinib concentrations were analyzed by HPLC. Following a single dose of 25 mg/kg, the averaged maximum plasma concentration (Cmax) of lapatinib in cats was 0.47 µg/mL and achieved at 7.1 hr post-administration, while the Cmax in dogs was 1.63 µg/mL and achieved at 9.5 hr post-administration. The mean elimination half-life was 6.5 hr in cats and 7.8 hr in dogs. The average area under the plasma concentration-time curve of dogs (37.2 hr·µg/mL) was significantly higher than that of cats (7.97 hr·µg/mL). These results exhibited slow absorptions of lapatinib in both animals after oral administration. The Cmax observed in cats was significantly lower and the half-life was shorter than those observed in dogs. Based on these results, a larger dose or shorter dosing intervals might be recommended in cats to achieve similar plasma concentration as dogs.

Histological and Molecular Characterization of the Inferior Olivary Nucleus and Climbing Fibers in the Goldfish, Carassius auratus.

The cerebellum receives inputs via the climbing fibers originating from the inferior olivary nucleus in the ventral medulla. In mammals, the climbing fibers entwine and terminate onto both major and peripheral branches of dendrites of the Purkinje cells. In this study, the inferior olivary nucleus and climbing fiber in the goldfish were investigated with several histological techniques. By neural tracer application to the hemisphere of the cerebellum, labeled inferior olivary neurons were found in the ventral edge of the contralateral medulla. Kainate stimulated Co + + uptake and gephyrin immunoreactivities were found in inferior olivary neurons, indicating, respectively, that they receive both excitatory (glutamatergic) and inhibitory (GABAergic or glycinergic) inputs. Inferior olivary neurons express vglut2.1 transcripts, suggesting they are glutamatergic. Around 85% of inferior olivary neurons were labeled with anti-calretinin antiserum. Calretinin immunoreactive (ir) climbing fiber terminal-like structures were distributed near the Purkinje cells and in the molecular layer. Double labeling immunofluorescence with anti-calretinin and zebrin II antisera revealed that the calretinin-ir climbing fibers run along and made synaptic-like contacts on the major dendrites of the zebrin II-ir Purkinje cells. In teleost fish, cerebellar efferent neurons, eurydendroid cells, also lie near the Purkinje cells and extend dendrites outward to intermingle with dendrites of the Purkinje cells within the molecular layer. Here we found no contacts between the climbing fiber terminals and the eurydendroid cell dendrites. These results support the idea that Purkinje cells, but not eurydendroid cells, receive strong inputs via the climbing fibers, similar to the mammalian situation.

A case of a dog with paragonimiasis after consumption of raw deer meat.

A 6-year-old castrated male Cavalier King Charles Spaniel was referred to the Animal Medical Center, Tokyo University of Agriculture and Technology, for examination and treatment of recurrent pneumothorax. Chest radiography and computed tomography showed multiple cavitary lesions in the caudal right posterior lobe. These lesions were surgically excised via thoracotomy. Subsequent histopathological examination revealed paragonimiasis. In the postoperative review, we found that the owner had fed raw deer meat to the dog four months earlier. Deer meat has attracted attention as a source of Paragonimus in humans. To our knowledge, this is the first report of Paragonimus infection in a dog due to deer meat consumption.

Efficacy of cilostazol in canine bradyarrhythmia.

Recently, cilostazol, a phosphodiesterase III inhibitor, has been described as alternative medical treatment for canine bradyarrhythmia in cases for which pacemaker implantation was not indicated or available. In this retrospective study, we investigated the use and efficacy of cilostazol in dogs with bradyarrhythmia in Japan. Dogs that had been brought to the Tokyo University of Agriculture and Technology Animal Medical Center and 23 veterinary hospitals in Japan and been treated with cilostazol initially as the only therapeutic strategy for bradyarrhythmia between January 2010 and August 2021 were included in this study. Survival analyses were performed using Cox proportional hazards analysis, the log-rank test, and the generalized Wilcoxon test to evaluate the efficacy of cilostazol. Fifty-nine privately owned dogs were included in this study. In the survival time analysis, the risk of death was significantly lower and the survival rate was higher in cases in which cilostazol was administered at 10 mg/kg or more per dose. A third-degree atrioventricular block also significantly increased the risk of death and was associated with a lower survival rate. However, in some patients with a third-degree atrioventricular block, there was an increase in the ventricular rate and improvement in clinical symptoms without disappearance or decrease of the atrioventricular block. This study had several important findings that have not previously been reported concerning the use of cilostazol for canine bradyarrhythmia, including the appropriate dose in a clinical setting and the efficacy and prognosis according to the type of bradyarrhythmia.

Evaluation of the Safety and Feasibility of Apheresis in Dogs: For Application in Metastatic Cancer Research.

In patients with solid tumors, circulating tumor cells (CTCs) spread in their blood and function as a seed for metastases. However, the study of CTCs has been limited by their rarity, low frequency, and heterogeneity. The efficient collection of CTCs will contribute to further research of metastatic cancers. Apheresis is a process in which the whole blood of an individual is passed through a machine that isolates a particular constituent and returns the remainder to the circulation. In the present study, we investigated the safety and feasibility of apheresis to separate peripheral blood monocytes (PBMCs), whose density is closely similar to that of CTCs, and to capture intravenously administered human breast cancer cells, MCF7s, from the dogs. No life-threatening events were observed in dogs during the apheresis process. The changes in the hemogram were transient and recovered gradually within a few days after apheresis. During apheresis, 50 mL of PBMCs could be collected from each dog. Notably, a thrombus was formed along the circuit wall during apheresis, which decreased the blood collection pressure. MCF7 cells were successfully captured by the apheresis machine. The captured cells were regrown in vitro and characterized compared with the original cells. In conclusion, apheresis could be safely performed in dogs to isolate CTCs with precautions to maintain hemodynamic stability.

Open heart mitral valve replacement using the Edwards-Sapien 3 for severe mitral annular calcification prevents left ventricular outflow tract obstruction.

Open heart transcatheter mitral valve implantation using the Edwards-Sapien 3 for mitral annular calcification is a safe procedure, because surgeons do not have to decalcify. And also, surgeons can resect the anterior mitral leaflet to prevent left ventricular outflow tract obstruction and deploy the valve under direct visualization.

Open-heart transseptal transcatheter mitral valve implantation with mitral annular calcification.

Mitral valve replacement (MVR) using a prosthesis of transcatheter aortic valve implantation for mitral annular calcification (MAC) is an alternative procedure which is very different from a conventional MVR and is safe. Acceptable results including mortality and morbidity have been reported. We report the case of a male patient treated with this procedure. There was a risk of left ventricular rupture due to extensive decalcification, so we performed transcatheter mitral valve implantation (TMVI). Since he had a history of surgical aortic valve replacement (AVR), we chose open-heart transseptal approach so as not to interfere with the aortic prosthesis. TMVI has a risk of an iatrogenic left ventricular outflow tract (LVOT) obstruction. Using open-heart transseptal approach, we could easily check an anterior commissure of mitral annulus to prevent LVOT obstruction. .

Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy.

Local cryotherapy is widely used as a treatment for sports-related skeletal muscle injuries. The molecular mechanisms are unknown. To clarify these mechanisms, we applied one to three 15-min cold stimulations at 4 °C to various cell lines (in vitro), the tibialis anterior (TA) muscle (ex vivo), and mouse limbs (in vivo). In the in vitro assay, cyclic AMP (cAMP) response element binding protein 1 (CREB1) was markedly phosphorylated (p-CREB1), and the CREB-binding protein (CBP) was recruited to p-CREB-1 in response to two or three cold stimulations. In a reporter assay with the cAMP-responsive element, the signals significantly increased after two to three cold stimulations at 4 °C. In the ex vivo study, CREB-targeting genes were significantly upregulated following two or three cold stimulations. The in vivo experiment disclosed that cold stimulation of a mouse limb for 9 days significantly increased mitochondrial DNA copy number and upregulated genes involved in mitochondrial biogenesis. The results suggest that local cryotherapy increases CREB transcription and upregulates CREB-targeting genes, in a manner dependent on cold stimulation frequency and duration. This information will inform further investigations into local cryotherapy as a treatment for sports-related skeletal muscle trauma.

Estimation of plastic marine debris volumes on beaches using unmanned aerial vehicles and image processing based on deep learning.

Plastic marine debris (PMD) is of global concern. To help address this problem, a novel approach for estimating PMD volumes using a combination of unmanned aerial vehicle (UAV) surveys and image processing based on deep learning is proposed. A three-dimensional model and orthoscopic image of a beach, constructed via Structure from Motion software using UAV-derived data, enabled PMD volumes to be computed by edge detection through image processing. The accuracy of the method was verified by estimating the volumes of test debris placed on a beach in known sizes and shapes. The proposed approach shows potential for estimating PMD volumes with an error of <5%. Compared with subjective methods based on beach surveys, this approach can accurately, rapidly, and objectively calculate the PMD volume on a beach and can be used to improve the efficiency of beach surveys and identify beaches that need preferential cleaning.

Association between false lumen segmental arteries and spinal cord ischemia in type A acute aortic dissection.

BACKGROUND: Spinal cord ischemia (SCI) and paraplegia are complications of surgery for type A acute aortic dissection (TAAAD). Since the segmental arteries play a key role in SCI, this study evaluated the association between SCI and false lumen segmental arteries (FLSAs: segmental arteries originating from the false lumen). METHODS: The study included 101 consecutive TAAAD patients (mean age, 66±13; range, 34-89 years) who underwent surgery from January 2011 to April 2017. The diagnosis of TAAAD and the number of FSLAs were determined by preoperative computed tomography (CT). Patients were divided into two groups according to the number of FLSAs at the Th9-L2 level: Group A (N.=13), ≥8 FLSAs; and group B (N.=88), ≤7 FLSAs. Preoperative, perioperative, and postoperative findings were compared between the groups, and risk factors for SCI were evaluated. RESULTS: The frequency of preoperative paralysis was significantly higher in Group A than Group B (P=.0070). The overall incidence of postoperative SCI was 8% (8/101) and significantly higher in Group A than Group B (5/13 [45%] vs. 3/88 (4%), P<0.0001). Hospital mortality was 8% (8/101) and significantly higher in Group A than Group B (3/13 [23%] vs. 5/88 [6%], P=.0302). Multivariate analysis showed that the independent risk factors for SCI were ≥8 FLSAs at Th9-L2 (odds ratio [OR], 20.4; 95% confidence interval [95% CI], 3.34-124.9, P=0.0011) and diabetes mellitus (OR, 22.3; 95% CI, 1.69-294.5; P=0.0184). CONCLUSIONS: In patients who underwent surgery for TAAAD, ≥8 FLSAs at the Th9-L2 levels on preoperative CT was a risk factor for SCI.

The long-term outcomes of partial arch repair using the frozen elephant trunk technique for distal arch aortic aneurysm.

PURPOSE: The purpose of this study was to evaluate the long-term results of partial arch repair using the frozen elephant trunk (FET) technique for distal arch aortic aneurysm and to examine the late complications. METHODS: Thirty-eight patients with true distal arch aortic aneurysms were repaired with FET introduced through an incision in the proximal arch aorta. Follow-up computed tomography was performed every 6 or 12 months in 36 surviving patients. The maximum dimension of the excluded aneurysmal space was measured to determine whether the aneurysmal space had decreased or disappeared. Late complications were also evaluated during the long-term follow-up. RESULTS: There was 1 hospital death (2.6%) and 1 (2.6%) case of paraplegia. There were 2 late sudden deaths (5.2%) thought to be due to aneurysm rupture and arrhythmia. Postoperative serial-computed tomography showed shrinkage of the excluded aneurysmal space in 33 of 36 patients. Late aneurysmal formation occurred in the anastomotic site in three patients. One patient underwent thoracic endovascular stent grafting 10 years after surgery, 1 patient had total arch replacement 9 years after surgery, and 1 died due to rupture. CONCLUSION: Frozen elephant trunk was found to be a useful alternative for treating true distal arch aortic aneurysm. However, we must be alert for late aneurysmal formation at the incision site.

Abdominal organ protection strategy for aortic arch aneurysm surgery.

INTRODUCTION: Body temperature maintained during open distal anastomosis in patients who undergo aortic surgery has been showing an upward trend; however, a higher temperature may increase visceral organ and spinal cord injury. Distal perfusion may reduce abdominal organ injury, especially acute kidney injury (AKI). METHODS: From 2009 to 2016, 56 patients who underwent ascending aortic and/or aortic arch surgery were enrolled. Open distal anastomosis was performed using one of three protection strategies: 1) systemic temperature of 25°C followed by selective cerebral perfusion (SCP) with lower body circulatory arrest (Group CA25, n=27); 2) systemic temperature of 28°C followed by SCP with lower body circulatory arrest (Group CA28, n=4); and 3) systemic temperature of 28°C followed by SCP with distal aortic perfusion (Group DP, n=25). RESULTS: During the postoperative course, levels of blood urea nitrogen, creatinine, liver enzymes, lactate dehydrogenase and lactate in Groups CA28 and CA25 were significantly higher than those in Group DP. AKI defined by the AKI Network occurred in 28 cases (50%) and 3 cases required permanent hemodialysis. AKI was significantly higher in Groups CA25 and CA28 than in Group DP (p=0.026). Mid-term follow-up showed that patients who developed postoperative AKI were more likely to suffer from cardiovascular events. CONCLUSIONS: Distal perfusion during open distal anastomosis reduced kidney and liver injury after thoracic aortic surgery despite an increased body temperature of up to 28°C. This strategy may be useful to prevent AKI, liver dysfunction, the need for hemodialysis and multiple organ failure and could improve mid-term results.

Effects of extracellular lactate on production of reactive oxygen species by equine polymorphonuclear leukocytes in vitro.

OBJECTIVE: To evaluate effects of extracellular lactate on viability, shape change, lactate metabolism, and reactive oxygen species (ROS) production in equine polymorphonuclear leukocytes (PMNs). SAMPLE: PMNs isolated from equine venous blood samples. PROCEDURES: PMNs were incubated with 0 to 300mM lactate for 30 minutes before each experiment. Viability was assessed via trypan blue exclusion. Shape change was assessed via flow cytometry and light microscopy. Relative quantification of monocarboxylic acid transporter and lactate dehydrogenase lactate dehydrogenase (LDH) isotype mRNAs was performed with a real-time PCR assay. Effects of lactate at a pH of 7.4 to 6.0 on ROS production in response to phorbol 12-myristate 13-acetate, opsonized zymosan, or N-formyl-methionyl-leucyl-phenylalanine was assessed by luminol-dependent chemiluminescence. RESULTS: Lactate had no effect on viability of PMNs but did alter their size and density. Monocarboxylic acid transporter 1 and lactate dehydrogenase B mRNA values were not altered. Monocarboxylic acid transporter 4 and lactate dehydrogenase A mRNA values were significantly decreased. Lactate incubation of cells significantly decreased PMN-derived luminol-dependent chemiluminescence and induced different sensitivities to stimulants (phorbol 12-myristate 13-acetate, opsonized zymosan, and N-formyl-methionyl-leucyl-phenylalanine). The response ratio to N-formyl-methionyl-leucyl-phenylalanine revealed that PMNs were primed by incubation with up to 50mM lactate, significantly increasing the production of ROS. Incubation with lactate and acidic pH caused a synergistic effect on ROS production. CONCLUSIONS AND CLINICAL RELEVANCE: Extracellular lactate potentially has a direct effect on the capacity to produce ROS by equine PMNs, which may be associated with alterations in innate immune functions within a short period after high-intensity exercise.