2‐(4‐Bromo‐2,5‐dimethoxyphenyl)‐N‐(2‐methoxybenzyl)ethanamine (25B‐NBOMe) is a substituted phenethylamine, which has become highly prevalent worldwide since 2014. Recently, in an autopsy case ...involving fatal 25B‐NBOMe intoxication, we found the postmortem increase of 25B‐NBOMe concentration in the cardiac blood approximately 2 days after death. The aim of this study was to investigate the distribution of 25B‐NBOMe and reproduce the postmortem redistribution using a rat model. Sprague‐Dawley rats were killed 30 min after intraperitoneal injection of 25B‐NBOMe (0.5 mg/kg) and left for 0, 3, 6, 9, 15, or 24 h (six rats at each time point). Postmortem 25B‐NBOMe concentrations in the cardiac blood increased by more than 10‐fold at 6‐h postmortem. 25B‐NBOMe accumulated primarily in the lung. Moreover, this postmortem redistribution occurred even in rats that had died 1 week following the 25B‐NBOMe administration. These findings indicate that attention should be paid to sample collection and data interpretation in the toxicological analysis of 25B‐NBOMe.
Purpose We evaluated electrical stimulation combined with pelvic floor muscle training for urinary incontinence after radical prostatectomy in a randomized controlled study. Materials and Methods A ...total of 56 men with severe urinary incontinence (more than 200 gm daily), mean ± SD age 66.6 ± 6.2 years, were randomized to an active treatment group (26) or a sham group (30). All patients performed pelvic floor muscle training preoperatively and continued throughout the study. For active stimulation 50 Hz square waves of 300 μs pulse duration and a 5 seconds on, 5 seconds off duty cycle were applied for 15 minutes twice daily with an anal electrode. Sham stimulation was limited to 3 mA with a 2 seconds on, 13 seconds off duty cycle. Results In the active group 8 (36%), 14 (63%), 18 (81%) and 19 (86%) patients were continent (22) vs 1 (4%), 4 (16%), 11 (44%) and 17 (86%) in the sham group (25) (leakage less than 8 gm daily) after 1, 3, 6 and 12 months, respectively. There was a significant difference in the number of continent patients between the groups at 1, 3 and 6 months (p = 0.0161, p = 0.0021 and p = 0.0156, respectively). The time to achieve continence was significantly shorter in the active group (2.71 ± 2.6 months) than in the sham group (6.82 ± 3.9 months, p = 0.0006). Changes in the amount of leakage, the International Consultation on Incontinence Questionnaire-Short Form score and the King's Health Questionnaire score were significantly larger in the active group at 1 month but there was no difference at 12 months. Conclusions Electrical stimulation resulted in earlier recovery of continence in patients with urinary incontinence after radical prostatectomy.
Aim: Mitochondrial damage and subsequent oxidative stresses play important roles in the pathogenesis of sepsis‐induced organ failure. Recently, autophagy, the major degradation pathway involved in ...mitochondrial quality control, was reported as a cellular adaptive response to oxidative stresses. The aim of the present study was to elucidate the molecular mechanism that underlies hepatic damage during lipopolysaccharide (LPS) treatment. We also try to determine if the damage can be attenuated by administration of cobalt protoporphyrin (CoPP), a potent heme oxygenase‐1 (HO‐1) inducer.
Methods: Five‐week‐old male Sprague–Dawley rats were injected i.p. with 15 mg/kg LPS. To determine if hepatic damage following LPS administration can be attenuated by HO‐1, CoPP was injected s.c. for 4 days consecutively at 24‐h intervals. After treatment with LPS, the liver was obtained and analyzed.
Results: A large reduction in liver mitochondrial protein and induction of autophagy were observed in LPS‐treated rats. Electron microscopic and immunohistochemical analyses demonstrated autophagic vacuoles in LPS‐treated rat liver. Oxidative stress markers (4‐hydroxy‐2‐nonenal and 8‐hydroxy‐2′‐deoxyguanosine) were increased in LPS‐treated animals; CoPP treatment ablated these alterations. An inhibitor for the opening of mitochondrial permeability transition pore, cyclosporine A, suppressed oxidative stress as well as liver damage during LPS administration. CoPP promoted autophagy and prevented rats from liver damage during LPS administration.
Conclusion: HO‐1 promotes autophagy and elimination of damaged mitochondria thereby repressing oxidative stress in LPS‐treated rat liver, revealing a novel mechanism for protection by HO‐1 against septic liver damage.
Purpose
Caffeine, a major ingredient of coffee and other drinks, causes minimal health problems. However, excessive caffeine intake may induce emotional and cardiac events. Studies on zebrafish ...larvae are considered useful for understanding drug poisoning because they can be used for multiple simulations.
Methods
The locomotion (swim distance) of zebrafish larvae exposed to varying concentrations of caffeine was measured using a light–dark test and an automatic video-tracking system. Mortality and heart rates were assessed 4 and 24 h after caffeine exposure and 24 h after caffeine removal.
Results
The heart and survival rates were reduced by exposure to caffeine of > 300 mg/L after 24 h in a dose-dependent manner; this was attenuated by caffeine removal at 4 h. Caffeine reduced the heart rate and survival considerably at 1000 mg/L, supporting the notion of caffeine-induced cardiac arrest resulting from bradycardia. The locomotion of zebrafish larvae during six alternating cycles of light–dark exposure was slower during light periods and faster during dark periods; 100–300 mg/L caffeine increased and decreased locomotion during light and dark cycles, respectively, with high inter-cycle reproducibility.
Conclusions
Given the anxiogenic effect of caffeine and light preference of zebrafish larvae, caffeine-induced changes in light–dark cycles could provide a new reliable marker for anxiety. Therefore, the “light–dark locomotion test” employed in this study is valuable for research on anxiogenic or anxiolytic substances. The test may allow simultaneous and automatic analysis of the locomotion of many fish under multiple conditions, thereby enabling evaluation of dose–response effects of caffeine.
Intermittent hypoxia (IH) has been associated with skeletal growth. However, the influence of IH on cartilage growth and metabolism is unknown. We compared the effects of IH on chondrocyte ...proliferation and maturation in the mandibular condyle fibrocartilage and tibial hyaline cartilage of 1-week-old male Sprague-Dawley rats. The rats were exposed to normoxic air (n = 9) or IH at 20 cycles/h (nadir, 4% O
; peak, 21% O
; 0% CO
) (n = 9) for 8 h each day. IH impeded body weight gain, but not tibial elongation. IH also increased cancellous bone mineral and volumetric bone mineral densities in the mandibular condylar head. The mandibular condylar became thinner, but the tibial cartilage did not. IH reduced maturative and increased hypertrophic chondrocytic layers of the middle and posterior mandibular cartilage. PCR showed that IH shifted proliferation and maturation in mandibular condyle fibrocartilage toward hypertrophic differentiation and ossification by downregulating TGF-β and SOX9, and upregulating collagen X. These effects were absent in the tibial growth plate hyaline cartilage. Our results showed that neonatal rats exposed to IH displayed underdeveloped mandibular ramus/condyles, while suppression of chondrogenesis marker expression was detected in the growth-restricted condylar cartilage.
Keloids have been treated by using radiation for over a century, and it is currently suggested that keloids are best treated by a combination of surgery and postoperative radiation therapy, although ...randomized controlled trials testing this are still lacking. However, plastic surgeons tend to avoid radiation therapy for keloids for fear of inducing malignant tumors. Thus, the authors searched for previous reports of associations between carcinogenesis and keloid radiation therapy, and examined the evidence-based opinions of radiation oncologists regarding the acceptability of using radiation to treat keloids.
A computerized literature search was carried out using PubMed that included citations from MEDLINE and PubMed Central between 1901 and March of 2009. The following search terms were used: "keloid(s)," "hypertrophic scar(s)," "radiation," "radiation therapy," "radiotherapy," "carcinogenesis," "carcinoma," "cancer," "complications," and "side effects." Moreover, the references for each report were also retrieved.
The authors located five cases of carcinogenesis (i.e., fibrosarcoma, basal cell carcinoma, thyroid carcinoma, and breast carcinoma) that were associated with radiation therapy for keloids. However, it was unclear whether an appropriate dose of radiation was used and whether sufficient protection of surrounding tissues was provided. Moreover, a questionnaire study of radiation oncologists around the world revealed that approximately 80 percent considered radiation to be acceptable for treating keloids.
The authors conclude that the risk of carcinogenesis attributable to keloid radiation therapy is very low when surrounding tissues, including the thyroid and mammary glands, especially in children and infants, are adequately protected, and that radiation therapy is acceptable as a keloid treatment modality.
To present mature results of high-dose-rate brachytherapy (HDR-BT) as monotherapy for intermediate- and high-risk prostate cancer.
From 1995 through 2012, 190 patients, 79 with intermediate-risk and ...111 with high-risk prostate cancer, were treated with HDR-BT alone using 48 Gy/8 fractions, 54 Gy/9 fractions, or 45.5 Gy/7 fractions over 4 to 5 days. Neoadjuvant with or without adjuvant androgen deprivation therapy was administered to 139 patients, 35 intermediate- and 104 high-risk.
Median follow-up time was 92 months (range, 10-227 months), with a minimum of 2 years for surviving patients. Respective rates of cause-specific survival, overall survival, metastasis-free survival, and biochemical no evidence of disease for the intermediate-risk patients were 100%, 100%, 96%, and 93% at 5 years, and 100%, 96%, 91%, and 91% at 8 years. Corresponding rates for the high-risk patients were 97%, 93%, 84%, and 81% at 5 years, and 93%, 81%, 74%, and 77% at 8 years. The cumulative incidence of late grade 2 to 3 genitourinary toxicity was 5% at 5 years and 10% at 8 years, and that of late grade 3 was 0 at 5 years and 1% at 8 years. The cumulative incidence of late grade 2-3 gastrointestinal toxicity was 4% at 5 years and 6% at 8 years, and that of late grade 3 was 0 at 5 years and 2% at 8 years. No grade 4 or 5 toxicity was detected.
Our single-institution study with a median 8-year follow-up showed that HDR-BT as monotherapy was safe and effective for patients with intermediate- and high-risk prostate cancer.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity. It is also the major regulator of antioxidants and has a pivotal role in tumor ...cell proliferation and resistance to chemotherapy. Accordingly, we investigated the role of Nrf2 in renal cell carcinoma (RCC).
In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression.
Targeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene. The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A/A. Nrf2 mutation and the C/A or A/A genotypes were significantly associated with increased Nrf2 protein expression (p = 0.0184 and p = 0.0005, respectively). When the primary tumor showed Nrf2 gene mutation, the C/A or A/A genotype, or elevated Nrf2 protein expression, the response of metastases to vascular endothelial growth factor-targeting therapy was significantly worse (p = 0.0142, p = 0.0018, and p < 0.0001, respectively), and overall survival was significantly reduced (p = 0.0343, p = 0.0421, and p < 0.0001, respectively). Elevated Nrf2 protein expression was also associated with shorter survival according to multivariate Cox proportional analysis.
These findings suggest an associated between progression of RCC and Nrf2 signaling.
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