Effects of antihistamines,ebastine and terfenadine,on electrocardiogram in conscious dogs and cats

The purpose of this study was to evaluate the effects of ebastine and terfenadine on the electrocardiogram of conscious dogs and cats. In dogs, terfenadine at oral doses of 30 mg/kg twice a day for 7 days prolonged the electrocardiographic QT interval and the corrected QT (QTc) interval on the seventh day, whereas the drug did not affect these parameters on the first day. Plasma concentrations of terfenadine and its active metabolite, fexofenadine, reached 306 and 8,541 ng/mL, respectively, on the seventh day. Ebastine at oral doses of 30 and 100 mg/kg once a day for 7 days was without effect on the QT and QTc intervals, whereas the drug slightly shortened the RR interval. On the seventh day following the dose of 100 mg/kg, plasma concentrations of ebastine and its active metabolite, carebastine, reached 36 and 1,939 ng/mL, respectively. In conscious cats, terfenadine at oral doses of 30 mg/kg twice a day for 7 days prolonged the QT and QTc intervals, QRS duration, JT and the corrected JT intervals. Unexpectedly, terfenadine induced ventricular tachyarrhythmia and premature beats. On the other hand, ebastine at oral doses of 100 mg/kg once a day for 7 days was without effect on the electrocardiographic parameters in cats. These results suggest that the electrocardiographic changes indicative of the proarrhythmic potential of terfenadine can be evaluated in conscious dogs and especially in conscious cats by repeated oral administration, and that ebastine does not induce such changes. 58:209–217, 2003. © 2003 Wiley‐Liss, Inc.     

Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer.

PURPOSE: The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 expression in human non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Clinicopathologic features and immunohistochemical expression of Skp2 and p27 proteins were studied in 138 patients with NSCLC. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. To analyze the role of Skp2 in vitro, NSCLC cells were transfected with an Skp2-expressing vector or small interfering RNA. RESULTS: Skp2 was overexpressed in males, smokers, patients with squamous cell carcinomas, and patients with poorly differentiated cancers (P = .034, < .0001, < .0001, and .002, respectively). The multivariant analysis revealed that Skp2 expression is an independent prognostic factor for survival in NSCLC. An inverse relationship of Skp2 with p27 expression was observed (P = .012), and patients with both a higher expression of Skp2 and a lower expression of p27 showed a significantly unfavorable prognosis (P = .0002). In vitro ectopic expression of Skp2 in NSCLC cells reduced the protein level of p27. Conversely, induction of Skp2 siRNA increased the protein level of p27, leading to growth inhibition in NSCLC cells. CONCLUSION: Skp2 overexpression is closely associated with the suppression of p27 and the aggressiveness in NSCLC. It also could be a therapeutic target in NSCLC.     

Electroconvulsive seizures increase the expression of MAP kinase phosphatases in limbic regions of rat brain.

The mitogen-activated protein (MAP) kinase cascades regulate a variety of cellular activities, including cell growth, proliferation, and apoptosis, and are reported to play a role in the actions of antidepressant treatment. There are a number of different classes of protein phosphatases that could influence the MAP kinase cascade. One of these, the MAP kinase phosphatase (MKP) family, is known to play a key role in dephosphorylation of activated MAP kinase. In the present study, we analyzed the expression of the MKP1, MKP2, and MKP3 isoforms in rat brain after electroconvulsive seizure (ECS), considered the most effective treatment for depression. In situ hybridization analysis demonstrates that ECS differentially regulates the expression of the MKP isoforms. Expression of MKP1 mRNA is robustly increased by acute ECS in the major cell layers of the hippocampus, including the dentate gyrus granule cell layer and the CA1 and CA3 pyramidal cell layers. In contrast, MKP2 is induced mainly in the dentate gyrus and MKP3 is preferentially increased in the CA1 and CA3 cell layers. In the prefrontal cortex, all three MKP isoforms are upregulated by acute ECS administration. Chronic ECS resulted in a similar pattern of induction for each of the MKP subtypes, demonstrating that there is little or no desensitization of the response to repeated ECS. The induction of MKP expression serves as negative feedback control for the MAP kinase cascades. Upregulation of MKP expression could dampen the actions of ECS, indicating that blockade of the MKPs could enhance the actions of antidepressant treatment.     

Prolonged oral treatment with an essential amino acid L-leucine does not affect female reproductive function and embryo-fetal development in rats.

L-leucine, an essential amino acid, is one of the most popular ingredients in dietary supplements. To investigate a possibility of its embryo-fetal toxicity in rats, 11- to 12-week old dams were orally administered an aqueous solution of L-leucine at doses of 300 or 1000 mg/kg body weight on gestational days 7-17. Body weight and feed intake was evaluated throughout the whole course of pregnancy (days 0-20). L-Leucine did not influence body weight, but at a dose of 1000 mg/kg, slightly enhanced feed intake on days 14 and 18 of pregnancy. Caesarean section (day 20) revealed no influences on the litter size and weight of live-born fetuses, the number of corpora lutea, implantation index or the quality of placenta, and the minor increase in feed intake was considered irrelevant to the pregnancy outcomes. Fetuses were evaluated in a battery of external, visceral and skeletal examinations. No effects of L-leucine on gender ratio and external abnormalities, and no significant treatment-related variations in visceral and skeletal pathologies were observed. These results suggested that L-leucine, administered orally during organogenesis at doses up to 1000 mg/kg body weight, did not affect the outcome of pregnancy and did not cause fetotoxicity in rats.     

Left Ventricular Abnormality and Covert Atrial Fibrillation in Embolic Stroke of Undetermined Source

Aims: The relationship between left ventricular (LV) function and AF detection in embolic stroke of undetermined source (ESUS) patients with insertable cardiac monitors (ICMs) remains unclear. We investigated the association between LV function and AF detection in patients with ESUS after ICMs implantation. Methods: We enrolled patients with ESUS who underwent ICMs implantation from September 2016 to September 2020 using a single-center, prospective registry. LV systolic and diastolic functions were assessed on precordial echocardiography by LV fractional shortening (LVFS) and average E/e’, respectively. Associations between characteristics of LV function and detection of AF by ICMs were analyzed. Results: Participants comprised 101 patients (median age, 74 years; male, 62%). During a median follow-up period of 442 days (interquartile range (IQR), 202–770 days), AF was detected in 24 patients (24%). Median duration from ICMs implantation to AF detection was 71 days (IQR, 13–150 days). When LVFS and E/e’ were dichotomized by cutoff value, each of low LVFS (＜35.5%; adjusted hazard ratio (HR), 4.77; 95% confidence interval (CI), 1.77–12.9) and high E/e’ (≥ 8.65; adjusted HR, 4.56; 95%CI, 1.17–17.7) were independently associated with AF detection after adjusting for age and sex. When patients were divided into four groups according to dichotomized LVFS and E/e’, the combination of low LVFS and high E/e’ was independently associated with AF. Conclusions: In patients with ESUS after ICMs implantation, the LV characteristics of low LVFS and high E/e’ were associated with AF detection.     

Neuromuscular electrical stimulation in the intensive care unit prevents muscle atrophy in critically ill older patients: A retrospective cohort study

Critically ill patients in the intensive care unit (ICU) develop muscle atrophy and decreased physical function. Though neuromuscular electrical stimulation (NMES) therapy has been shown to be effective in preventing this, but its effect on older patients is unknown.To examine the course of critically ill older patients treated with NMES in the ICU and to define the impact of its use.A retrospective cohort study was conducted using older ICU patients (≥65 years) categorized into a control group (n = 20) and an NMES group (n = 22). For subgroup analysis, each group was further classified into pre-old age (65–74 years) and old age (≥75 years).The control group showed significant decrease in muscle thickness during ICU and hospital stay. The NMES group showed lower reduction in muscle thickness and showed decrease in muscle echo intensity during hospital stay, compared to the control group. NMES inhibited decrease in muscle thickness in the pre-old age group versus the old age group. The decreasing effect of NMES on echo intensity during hospital stay manifested only in the pre-old age group. We did not find much difference in physical functioning between the NMES and control groups.Lower limb muscle atrophy reduces in critically ill older patients (≥65 years) with NMES and is pronounced in patients aged < 75 years. The impact of NMES on the physical functioning of older patients in ICU needs to be further investigated.     

Label‐free multiphoton excitation imaging as a promising diagnostic tool for breast cancer

Histopathological diagnosis is the ultimate method of attaining the final diagnosis; however, the observation range is limited to the two‐dimensional plane, and it requires thin slicing of the tissue, which limits diagnostic information. To seek solutions for these problems, we proposed a novel imaging‐based histopathological examination. We used the multiphoton excitation microscopy (MPM) technique to establish a method for visualizing unfixed/unstained human breast tissues. Under near‐infrared ray excitation, fresh human breast tissues emitted fluorescent signals with three major peaks, which enabled visualizing the breast tissue morphology without any fixation or dye staining. Our study using human breast tissue samples from 32 patients indicated that experienced pathologists can estimate normal or cancerous lesions using only these MPM images with a kappa coefficient of 1.0. Moreover, we developed an image classification algorithm with artificial intelligence that enabled us to automatically define cancer cells in small areas with a high sensitivity of ≥0.942. Taken together, label‐free MPM imaging is a promising method for the real‐time automatic diagnosis of breast cancer.     

Ovarian Sertoli-Leydig cell tumor with heterologous gastrointestinal epithelium as a source of alpha-fetoprotein: a case report

Ovarian Sertoli-Leydig cell tumors (SLCT) are rare sex cord stromal neoplasms. To date there have been approximately 25 case reports of ovarian SLCT expressing alpha-fetoprotein (AFP). In such cases, AFP was immunohistochemically detected in the Sertoli cells, Leydig cells, or hepatocytes. This case report confirms heterologous gastrointestinal epithelium expression of AFP. A 20-year-old woman presented with complaints of abdominal enlargement and irregular menstrual cycles over one year. A right ovarian tumor was detected and the patient's serum AFP was elevated. A right salpingo-oophorectomy was performed. On microscopic examination, the tumor was composed of a fibrosarcoma-like area and a poorly differentiated SLCT area with heterologous gastrointestinal epithelium. Immunohistochemical analysis detected AFP in the gastrointestinal epithelium only. Postoperatively, serum AFP levels fell to normal. A recurrent tumor was discovered in the omentum after adjuvant chemotherapy, but serum AFP remained normal. A second laparotomy was performed and the recurrent tumor showed only fibrosarcoma-like features. The patient received second line chemotherapy and is currently in remission. This is the first case of AFP production by heterologous gastrointestinal epithelium in SLCT.