The role of arterial stiffness in the onset of Takotsubo cardiomyopathy observed with noradrenaline administration and intracranial blood injection in rabbits.

Takotsubo cardiomyopathy (TCM) has been reported to occur after subarachnoid hemorrhage, and the involvement of a critical activity of catecholamines has been mentioned, but the details of its onset have not been fully clarified. Recently, proper arterial stiffness could be measured with cardio-ankle vascular index. Therefore, we aimed to clarify the role of arterial stiffness in onset of TCM using rabbits under infusion of noradrenaline and injection of blood into brain ventricle. Rabbits were divided into three groups: infusion of noradrenaline (group A), infusion of noradrenaline + injection of saline into the brain ventricle (group B), infusion of noradrenaline + injection of blood in the brain ventricle (group C). Aortic arterial stiffness beta (Aß) and femoral arterial stiffness beta (Fß) were defined according to definition of the cardio-ankle vascular index. Blood pressure (BP), Aß, Fß, and femoral vessel resistance (FVR) were measured. Left ventricular movement were monitored with echocardiography. BP increased uniformly in all three groups. Fß in the group A, B and C increased from 3.6 ± 3.2, 3.6 ± 3.6 and 3.9_ ± 4.2 to 15 ± 2, 17.9 ± 2.4, 34.8 ± 9.1 due to the ICP enhancements in addition to noradrenaline administration, respectively. Fß in groups B and C was significantly larger than that in group A. On echocardiography, a much higher akinesic area of the apex was observed in group C compared with group A and B. Cardiac movements similar to TCM were observed slightly in group B and definitely in group C. Noradrenaline administration infusion and blood injection into the brain ventricle induced TCM accompanying with enhanced femoral arterial stiffness. These results suggested that elevated arterial stiffness might be involved in the formation of TCM in addition to a critical activity of catecholamines and an increase in intracranial pressure with blood injection.

The influence of hemorrhagic shock on ocular microcirculation by obtained by laser speckle flowgraphy in a white rabbit model.

PURPOSE: To clarify the continuous changes in the retinal vessels' and choroid's microcirculation during hemorrhagic shock and resuscitation in a rabbit model. METHODS: Hemorrhagic shock by the removal of blood (30 mL) and resuscitation by a blood-return technique was induced in anesthetized male New Zealand White rabbits (n = 10). We evaluated the retinal vessel blood flow (relative flow volume: RFV) and choroidal blood flow (mean blur rate in the choroid area: MBR-CH) by laser speckle flowgraphy (LSFG), with simultaneous measurements of systemic hemodynamics and laboratory parameters. RESULTS: RFV and MBR-CH showed significant decreases immediately after the initiation of blood removal and recovered by blood return. The lactate concentration tended to increase from baseline by the blood-removal operation, and it was significantly higher at the end of observation period. The %RFV and %MBR-CH each showed a significant positive correlation with mean arterial blood pressure, cardiac output, carotid blood flow, and central venous pressure. %RFV showed a significant positive correlation with %central venous oxygen saturation and negatively correlated with %lactate. The %hemoglobin did not show a significant correlation with %RFV or %MBR-CH. CONCLUSION: This rabbit hemorrhagic shock model confirmed that ocular microcirculation measurements by LSFG feasibly reflect variations in systemic hemodynamics during hemorrhagic shock and recovery.

[Clinical Complete Response to Definitive Chemoradiotherapy for Advanced Lower Rectal Cancer-A Case Report].

A man in his 80s was admitted to our hospital with a chief complaint of bloody stools. He was diagnosed with cT2N0M0, cStage Ⅰ rectal cancer. As the patient was of advanced age and had multiple comorbidities, definitive chemoradiotherapy was administered. Immediately after treatment, the patient achieved a complete clinical response, and recurrence has not been detected for 2 years and 3 months since treatment.

Physiological role of nitric oxide for regulation of arterial stiffness in anesthetized rabbits.

We assessed effects of acetylcholine and Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) on the cardio-ankle vascular index (CAVI), an indicator of arterial stiffness from origin of aorta to tibial artery, in halothane-anesthetized rabbits. Acetylcholine decreased the blood pressure, femoral vascular resistance and CAVI, whereas l-NAME did not affect the CAVI at a hypertensive dose. The acetylcholine-induced decrement of CAVI was completely suppressed by l-NAME. These results suggest that the arterial stiffness in rabbits may be independent from homeostatic production of nitric oxide, however, it can be decreased by large amounts of nitric oxide that are intrinsically produced by exogenously administered acetylcholine.

Angiotensin II acutely increases arterial stiffness as monitored by cardio-ankle vascular index (CAVI) in anesthetized rabbits.

The cardio-ankle vascular index (CAVI) has been established as a stiffness indicator from thoracic aorta to tibial arteries. To better understand physiological regulatory factors for the arterial stiffness, we assessed effects of angiotensin II and adrenaline on the CAVI in anesthetized rabbits. A hypertensive dose of angiotensin II (300 ng/kg, i.v.) increased the CAVI as well as the heart-ankle pulse wave velocity (haPWV). On the other hand, although a hypertensive dose of adrenaline (1000 ng/kg, i.v.) increased the haPWV, it did not affect the CAVI. These results suggest that angiotensin II may act as a regulatory factor for arterial stiffness.

Quality of life after external beam radiotherapy for localized prostate cancer: Comparison with other modalities.

In external beam radiotherapy for localized prostate cancer, acute toxicities are typically transient and mild. These symptoms will disappear within 4-8 weeks after external beam radiotherapy. Some patients might suffer from proctitis with bloody stools as late rectal toxicity. Therefore, it has been shown that external beam radiotherapy has a more pronounced negative impact on bowel function compared with other treatment modalities. However, the recent development of modern beam delivery techniques, including intensity-modulated radiotherapy, allows us not only to deliver higher doses to the prostate, but also to decrease the doses to the critical organs, resulting in the maintenance of patients' quality of life within satisfactory levels. Patients' quality of life after external beam radiotherapy is also strongly related to the total dose, fractionation regimens, dose parameters of the critical organs and treatment plan quality, with a trade-off between the radicality of external beam radiotherapy and potentially increased toxicity. Radiation oncologists should choose treatment parameters carefully to achieve a reasonable balance between a good oncological outcome and the patient's quality of life.

Patterns of radiotherapy infrastructure in Japan and in other countries with well-developed radiotherapy infrastructures.

BACKGROUND: In high-income countries, the number of radiotherapy machine per population reaches a sufficient level. However, the patterns of infrastructure of radiotherapy in high-income countries are not well known. METHODS: Among 29 high-income countries with gross national income of $25,000 or more per capita, we selected 23 countries whose total number of newly diagnosed cancer patients in 2012 was reported in the Organisation for Economic Co-operation and Development Health Statistics 2017. The numbers of radiotherapy centers and teletherapy machines in each of these 23 countries were collected using the Dictionary of Radiotherapy Centers database. RESULTS: The number of cancer patients per teletherapy machine was 452.35-1398.22 (median 711.66) with a three-fold variation, whereas the number of cancer patients per radiotherapy center varied even more widely, from 826.16 to 5159.86 (median 2259.83) with a six-fold variation. The average number of teletherapy machines per radiotherapy center also ranged widely, from 1.24 to 8.29 (median 3.11) with a seven-fold variation. The number of teletherapy machines in each country was almost proportional to that of cancer patients, and the number of teletherapy machines per radiotherapy center was inversely related to the number of radiotherapy centers per cancer patients. The number of teletherapy machines per radiotherapy center in Japan was 1.24, the most fragmented among the high-income countries. The percentage of large radiotherapy centers having three or more teletherapy machines in Japan was the smallest among 23 high-income countries. CONCLUSIONS: Optimization of the radiotherapy infrastructure in Japan should be carefully considered.

Functional expression and comparative characterization of four feline P450 cytochromes using fluorescent substrates.

1. Cytochrome P450s (CYP) are a major group of metabolizing enzymes for xenobiotics in humans and other mammals. The properties of CYP isoforms in the domestic cat, an obligate carnivore, are largely unknown at present. In this study, we studied relative expression in tissues and enzymatic properties of nine significant feline CYP isoforms. 2. CYP2E2 transcript was most abundant in the feline liver, followed by CYP2A13 and 2E1. Transcripts of CYP3A131, 1A2 and 1A1 were also present in the liver, while CYP2D6 and 3A132 were only slightly expressed. CYP3A131 was a major transcript in the small intestine. 3. Four major CYP isoforms in the feline liver and small intestine (CYP1A2, CYP2A13, CYP2E2 and CYP3A131) were heterologously expressed in Escherichia coli to generate functional monooxygenase systems. We carried out screenings of 17 test compounds known to be inhibitors of CYP isoforms in other mammals as well as two anticancer drugs to assess the activity modulation of feline CYP isoforms using fluorogenic substrates. These CYP isoforms showed similar selectivity to counterparts in other mammals against inhibitors as a whole but with many exceptions. 4. The present study suggests the usefulness of the feline CYP recombinant system to obtain chemical affinity information and possible drug interactions in CYP metabolism of domestic cats.

Characterization of feline cytochrome P450 2B6.

1. Little is known about drug metabolism in carnivores. Although the domestic cat (Felis catus) is an obligate carnivore and is the most common companion animal, usage and dosage of many drugs are determined according to information obtained from humans and dogs. We determined the complete cDNA sequence of CYP2B6 from the feline lung. 2. Feline CYP2B6 consists of 494 deduced amino acids, showing highest identity with the dog CYP2B ortholog, followed by those of horse, pig, primate and human. 3. Feline CYP2B6 transcripts were expressed predominantly in the lung and slightly in the small intestine but not in the liver without significant sex-dependent differences. Western blot analysis with an anti-human CYP2B6 antibody confirmed the presence of CYP2B protein in the lung but not in the liver. 4. Feline CYP2B6 proteins heterologously expressed in Escherichia coli metabolized several substrates specific to human CYP2B6, including 7-ethoxy-4-(trifluoromethyl) coumarin (EFC). The metabolic activity was strongly inhibited by medetomidine and atipamezole, potent inhibitors of canine CYP2B11 (now officially CYP2B6) as well as by ticlopidine and sertraline, inhibitors selective to human CYP2B6. 5. The results suggest that feline CYP2B6 is a functional CYP2B ortholog that plays a role in the local defense mechanism in the cat respiratory system and intestine.

Identification and functional characterization of novel feline cytochrome P450 2A.

1. Cytochrome P450s are the major metabolizing enzymes for xenobiotics in humans and other mammals. Although the domestic cat Felis catus, an obligate carnivore, is the most common companion animal, the properties of cytochrome P450 subfamilies are largely unknown. 2. We newly identified the feline CYP2A13, which consists of 494 deduced amino acids, showing the highest identity to CYP2As of dogs, followed by those of pigs, cattle and humans. 3. The feline CYP2A13 transcript and protein were expressed almost exclusively in the liver without particular sex-dependent differences. 4. The feline CYP2A13 protein heterogeneously expressed in Escherichia coli showed metabolic activity similar to those of human and canine CYP2As for coumarin, 7-ethoxycoumarin and nicotine. 5. The results indicate the importance of CYP2A13 in systemic metabolism of xenobiotics in cats.

Evaluating the relationship between ocular blood flow and systemic organ blood flow in hemorrhagic shock using a rabbit model.

This study aimed to investigate the feasibility of utilizing noninvasive ocular blood flow measurements as potential indicators of systemic circulation in rabbits experiencing hemorrhagic shock. Using Laser speckle flowgraphy, ocular blood flow indices, relative flow volume (RFV), and mean blur rate in the choroidal area (MBR-CH) were assessed in New Zealand White rabbits (n = 10) subjected to controlled blood removal and return. Hemodynamic parameters and biochemical markers were monitored alongside ocular circulation during blood removal and return phases. Additionally, correlations between ocular parameters and systemic indices were examined. The results indicated that RFV and MBR-CH exhibited significant correlations with renal and intestinal blood flows, with stronger correlations observed during blood removal. Additionally, ocular blood flow changes closely mirrored systemic dynamics, suggesting their potential as real-time indicators of shock progression and recovery. These findings indicate that ocular blood flow measurements may serve as real-time indicators of the systemic circulation status during hemorrhagic shock, offering potential insights into shock management and guiding tailored interventions. Thus, noninvasive ocular blood flow evaluation holds promise as an innovative tool for assessing systemic circulation dynamics during hemorrhagic shock.

Unique genomic sequences in a novel Mycobacterium avium subsp. hominissuis lineage enable fine scale transmission route tracing during pig movement.

Mycobacterium avium subsp. hominissuis (MAH) is one of the most prevalent mycobacteria causing non-tuberculous mycobacterial disease in humans and animals. Of note, MAH is a major cause of mycobacterial granulomatous mesenteric lymphadenitis outbreaks in pig populations. To determine the precise source of infection of MAH in a pig farm and to clarify the epidemiological relationship among pig, human and environmental MAH lineages, we collected 50 MAH isolates from pigs reared in Japan and determined draft genome sequences of 30 isolates. A variable number of tandem repeat analysis revealed that most pig MAH isolates in Japan were closely related to North American, European and Russian human isolates but not to those from East Asian human and their residential environments. Historical recombination analysis revealed that most pig isolates could be classified into SC2/4 and SC3, which contain MAH isolated from pig, European human and environmental isolates. Half of the isolates in SC2/4 had many recombination events with MAH lineages isolated from humans in East Asia. To our surprise, four isolates belonged to a new lineage (SC5) in the global MAH population. Members of SC5 had few footprints of inter-lineage recombination in the genome, and carried 80 unique genes, most of which were located on lineage specific-genomic islands. Using unique genetic features, we were able to trace the putative transmission route via their host pigs. Together, we clarify the possibility of species-specificity of MAH in addition to local adaptation. Our results highlight two transmission routes of MAH, one exposure on pig farms from the environment and the other via pig movement. Moreover, our study also warns that the evolution of MAH in pigs is influenced by MAH from patients and their residential environments, even if the MAH are genetically distinct.

Re-irradiation for metastatic brain tumors with whole-brain radiotherapy.

OBJECTIVE: To determine whether second whole-brain irradiation is beneficial for patients previously treated with whole-brain irradiation. METHODS: A retrospective analysis was done for 31 patients with brain metastases who had undergone re-irradiation. Initial whole-brain irradiation was performed with 30 Gy/10 fractions for 87% of these patients. Whole-brain re-irradiation was performed with 30 Gy/10 fractions for 42% of these patients (3-40 Gy/1-20 fractions). Three patients underwent a third whole-brain irradiation. RESULTS: The median interval between the initial irradiation and re-irradiation was 10 months (range: 2-69 months). The median survival time after re-irradiation was 4 months (range: 1-21 months). The symptomatic improvement rate after re-irradiation was 68%, and the partial and complete tumor response rate was 55%. Fifty-two percent of the patients developed Grade 1 acute reactions. On magnetic resonance imaging, brain atrophy was observed in 36% of these patients after the initial irradiation and 74% after re-irradiation. Grade ≥2 encephalopathy or cognitive disturbance was observed in 10 patients (32%) after re-irradiation. Based on univariate analysis, significant factors related to survival after re-irradiation were the location of the primary cancer (P = 0.003) and the Karnofsky performance status at the time of re-irradiation (P = 0.008). A Karnofsky performance status ≥70 was significant based on multivariate analysis (P = 0.050). CONCLUSIONS: Whole-brain re-irradiation for brain metastases placed only a slight burden on patients and was effective for symptomatic improvement. However, their remaining survival time was limited and the incidence of cognitive disturbance was rather high.

Real-Time Evaluation of Regional Arterial Stiffening, Resistance, and Ocular Circulation During Systemic Administration of Adrenaline in White Rabbits.

Purpose: To evaluate continuous variations of ocular microcirculation by laser speckle flowgraphy and those of regional stiffening by pulse wave velocity (PWV) and vascular resistance under systemic adrenaline administration in rabbits. Methods: Six 16-week-old male rabbits were evaluated. The mean blur rates in the retinal vessel (MBR-RV) and choroid (MBR-CH) were measured. We assessed blood pressure (BP), femoral and carotid vascular resistance, and the heart-ankle (ha)-PWV, heart-femoral (hf)-PWV, and femoral-ankle (fa)-PWV. Adrenaline (100, 300, and 1000 ng/kg) was intravenously administered over a 10-minute period during which the parameters were measured simultaneously every 2 minutes. Results: The MBR-RV and MBR-CH values were dose-dependently increased by the adrenaline in parallel with increased BP. At the load of 100 ng/kg adrenaline, the ΔMBR-RV and ΔMBR-CH showed positive correlations with the variation rate in mean arterial blood pressure. Also, the variation rate in carotid vascular resistance and the Δfa-PWV and Δhf-PWV were significantly positively correlated with both the ΔMBR-RV and ΔMBR-CH. At the 300-ng/kg phase, the correlations between the Δha-PWV and both ΔMBR-RV and ΔMBR-CH were canceled; instead, the Δhf-PWV showed a significant negative correlation with the ΔMBR-RV and ΔMBR-CH. At the 1000-ng/kg phase, Δha-PWV again showed significant positive correlations with the ΔMBR-RV and ΔMBR-CH. Conclusions: These results indicate the possibility that under a systemic administration of adrenaline in rabbits, not only the BP value but also the vascular resistance and arterial function are related to the variation in ocular microcirculation. Translational Relevance: A real-time evaluation system of systemic regional arterial function and ocular microcirculation in rabbits was developed.

Fatal suppurative meningoencephalitis caused by Klebsiella pneumoniae in two calves.

One calf died (No. 1) and another was euthanized following astasia (No. 2). Histopathological examination revealed suppurative meningoencephalitis in these calves. Klebsiella pneumoniae antigens were detected in lesions. Thymocytes were decreased in the thymus cortex in both cases. 16S rRNA gene sequencing of the No. 1 isolate and bacterial extracts from formalin fixed paraffin embedded sections of No. 2 revealed that both samples were K. pneumoniae. The No. 1 isolate showed multidrug resistance against penicillin antibiotics, fosfomycin, streptomycin, macrolide antibiotics, tetracycline antibiotics, and clindamycin. Immunosuppression is a significant septicemic K. pneumoniae infection risk factor. Our study provides new aspects regarding K. pneumoniae infections in cattle, bacterial meningoencephalitis differentiation, and K. pneumoniae and bacterial meningoencephalitis treatments.

The relationship between the quantitative evaluation of thyroid bed uptake and the disappearance of accumulation in adjuvant radioactive iodine therapy for differentiated thyroid cancer.

OBJECTIVE: Iodine-131 (I-131) radioactive iodine therapy (RAI) after total thyroidectomy is the standard treatment for patients with differentiated thyroid cancer (DTC). We investigated the relationship between the quantitative parameters of the iodine uptake and the disappearance of the accumulation in the thyroid bed in adjuvant therapy using a 1.11 GBq or 3.70 GBq dose of I-131. METHODS: We retrospectively analyzed the cases of 40 patients with DTC who were treated with RAI at our institution between April 2017 and August 2019. The patients were treated with the I-131 dose of 1.11 GBq (n = 25) or 3.70 GBq (n = 15) after total thyroidectomy. The I-131 whole-body scan and hybrid single-photon emission computed tomography/X-ray computed tomography (SPECT/CT) were performed 3 days after RAI. Using image analysis software, we measured the standardized uptake value (SUV) and absolute radioactivity concentration (kBq/ml) on the target lesions with the highest uptake in the thyroid bed. RESULTS: The median period from RAI to the evaluation of the absence of uptake of the thyroid bed was 6.75 months. After RAI, uptake of the thyroid bed disappeared in 26 of the 40 patients. The disappearance rate was significantly higher in the 3.70 GBq group than in the 1.11 GBq group (86.7% vs. 52.0%, respectively; p = 0.029). However, there were no significant differences in the values of kBq/ml or SUV between the 1.11 GBq group and 3.70 GBq group. On the other hand, the group in which the uptake disappeared after RAI showed significantly higher kBq/ml max and kBq/ml mean values than the group in which the uptake did not disappear after RAI (p = 0.028, p = 0.032, respectively). The SUVmax and SUVmean also tended to be higher in the disappeared-uptake group than the not-disappeared-uptake group, but the differences were not significant (p = 0.166, p = 0.176, respectively). CONCLUSIONS: The quantitative evaluation might be useful as one of the predictive indicators of the disappearance of the accumulation of radioactive iodine in the thyroid bed.

Genomic features of Mycobacterium avium subsp. hominissuis isolated from pigs in Japan.

Mycobacterium avium subsp. hominissuis (MAH) is one of the most important agents causing non-tuberculosis mycobacterial infection in humans and pigs. There have been advances in genome analysis of MAH from human isolates, but studies of isolates from pigs are limited despite its potential source of infection to human. Here, we obtained 30 draft genome sequences of MAH from pigs reared in Japan. The 30 draft genomes were 4,848,678-5,620,788 bp in length, comprising 4652-5388 coding genes and 46-75 (median: 47) tRNAs. All isolates had restriction modification-associated genes and 185-222 predicted virulence genes. Two isolates had tRNA arrays and one isolate had a clustered regularly interspaced short palindromic repeat (CRISPR) region. Our results will be useful for evaluation of the ecology of MAH by providing a foundation for genome-based epidemiological studies.

Common hepatic artery aneurysm treated with an endovascular stent-graft: a case report.

We present the case of a common hepatic artery aneurysm successfully treated with an endovascular stent-graft. Although the long-term usefulness of stent-graft placement is not confirmed, the favorable mid-term course in our patient suggests that stent-graft placement may be considered as the treatment of choice in selected cases with hepatic artery aneurysm.

Molecular cloning and expression of cytochrome P450 2D6 in the livers of domestic cats.

Cytochrome P450 2D (CYP2D) is one of the major metabolizing enzymes for drugs in humans and other mammals. Although domestic cats (Felis catus) are the most common companion animal in many countries, the properties of their drug-metabolizing system are largely unknown. We determined the complete cDNA sequence of the CYP2D open reading frame (1,500 bp) with both 5'- and 3'-untranslated regions in domestic cats. Feline CYP2D consists of 500 deduced amino acids and shows high homology with CYP2Ds of primates and rodents, particularly with the canine CYP2D homologue, and was designated as CYP2D6 based on its genomic structure. CYP2D6 transcripts were expressed predominantly in the liver and to a much lesser in the testis, suggesting the role of xenobiotic metabolism in the liver.