In vivo activity on murine tumors of a novel antitumor compound,N-β-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]phenazine-6-carboxamide sodium salt (NC-190)

Summary A novel antitumor compound, N--dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190) was evaluated for its antitumor activity in experimental murine tumor systems. In the initial studies with P388 leukemia (i.p.-i.p.), NC-190 led to an increase of >200% in life span (ILS), and 75% of the mice were alive on day 30, when the optimal dose (50 mg/kg, days 1–5) was given. Additionally, the compound had significant activities against i.p. inoculated mouse L1210 leukemia, B16 melanoma, M5076 reticulum cell sarcoma, sarcoma 180, mouse hepatoma MH134, and rat Yoshida sarcoma and Yoshida ascites hepatoma AH130. The optimal dose resulted in a >280% ILS with a 30-day survival of 50% in mice with L1210 leukemia (100 mg/kg, days 1–5), a 156% ILS in mice with B16 melanoma (50 mg/kg, days 1–5), a 98% ILS with a 90-day survival of 25% in mice with M5076 reticulum cell sarcoma (25 mg/kg, days 1, 5, 9, and 13), a >300% ILS with a 60-day survival of 50% in mice with sarcoma 180 (50 mg/kg, days 3–10), a 148% ILS with a 60-day survival of 25% in mice with MH134 (25 mg/kg, days 1–5), a 129% ILS with a 60-day survival of 12.5% in rats with Yoshida sarcoma (12.5 mg/kg, day 3–10), and a >161% ILS with a 60-day survival of 50% in rats with AH130 (6.3 mg/kg, days 3–10). In the experiments with s.c. inoculated tumors, NC-190 not only inhibited tumor growth, but also increased the life span of mice with Lewis lung carcinoma or B16 melanoma. The 60-day survivors accounted for 60% and 30% in mice with Lewis lung carcinoma and B16 melanoma, respectively. The compound significantly inhibited the spontaneous lung metastasis of Lewis lung carcinoma by more than 90% when eight daily i.v. injections were given. NC-190 was active by the i.p., s.c., and i.v. routes. Five consecutive daily i.p. doses (days 1–5) were more effective than a single dose (day 1), two doses (days 1 and 5), or three doses (days 1, 5, and 9). NC-190 warrants further study as a potential antineoplastic agent against human neoplasms, as it has a broad spectrum of antitumor activity and inhibits metastasis.Abbreviations ILS increase in life span - MST median survival time - MMC mitomycin C - ADM adriamycin - CPA cyclophosphamide - 5-FU 5-fluorouracil     

Coping strategies of family carers for older relatives in Finland

Background. As the population continues to age, it is important that older people and their family carers get all the help and support they need with coping. This requires knowledge and understanding of the factors that foster and promote coping strategies, and on the other hand that complicate coping. Aims and objectives. Conducted as part of a major international research project on carers’ work and coping in four countries, the purpose of this study was to explore the coping strategies of family carers looking after older relatives in their own home and to identify related factors. Design. A survey involving 290 family carers from three towns in Finland. Methods. The data were collected with a questionnaire including the Carers’ Assessment of Managing Index developed by Nolan et al. (1995) . Results. The most helpful coping strategy was to establish one's priorities and concentrate on them. Other strategies that over 80% of the respondents regarded as helpful were believing in oneself and one's ability to handle the situation, taking life 1 day at a time, looking for positive things in each situation and relying on one's own expertise and experience. The 10 most helpful coping methods included five problem‐solving strategies, four emotional‐cognitive strategies and one managing stress strategy. The age and gender of the family carers were found to correlate with the results. Conclusions. Our findings lend further support to earlier results according to which there are both similarities and differences in the coping strategies of family carers in different countries. Relevance to clinical practice. Nurses who meet family carers of ageing individuals in their work will be able to use these results in assessing how these carers are coping and whether they need support, as well as in developing services for family carers.     

Environmental enrichment stimulates progenitor cell proliferation in the amygdala

Enriched environments enhance hippocampal neurogenesis, synaptic efficacy, and learning and memory functions. Recent studies have demonstrated that enriched environments can restore learning behavior and long‐term memory after significant brain atrophy and neural loss. Emotional and anxiety‐related behaviors were also improved by enriched stimuli, but the effect of enriched environments on the amygdala, one of the major emotion‐related structures in the central nervous system, remains largely unknown. In this study, we have focused on the effects of an enriched environment on cell proliferation and differentiation in the murine amygdala. The enriched environment increased bromodeoxyuridine (BrdU)‐positive (newborn) cell numbers in the amygdala, almost all of which, immediately after a 1‐week period of enrichment, expressed the oligodendrocyte progenitor marker Olig2. Furthermore, enriched stimuli significantly suppressed cell death in the amygdala. Some of the BrdU‐positive cells in mice exposed to the enriched environment, but none in animals housed in the standard environment, later differentiated into astrocytes. Our findings, taken together with previous behavioral studies, suggest that progenitor proliferation and differentiation in the amygdala may contribute to the beneficial aspects of environmental enrichment such as anxiolytic effects. © 2009 Wiley‐Liss, Inc.     

Anterior capsular plaque in congenital cataract: occurrence, morphology, immunofluorescence, and ultrastructure

PURPOSE: To study occurrence, morphology, immunofluorescence, and ultrastructural features of congenital anterior capsular plaque (ACP) obtained from pediatric eyes undergoing cataract surgery. METHODS: Two hundred sixty consecutive pediatric eyes undergoing congenital cataract surgery were enrolled in the present study. Anterior lens epithelium from cataract without ACP and with ACP was collected. Wholemounts of lens epithelium were stained with hematoxylin-eosin. Five-micrometer-thick sections of large ACPs were subjected to immunofluorescence localization of collagen type I, collagen type IV, alpha-smooth muscle actin (alpha SMA), and alpha A-crystallin. Ultrathin sections were studied by transmission electron microscope. RESULTS: The overall occurrence of ACP in pediatric eyes undergoing congenital cataract surgery was 11.5%. The occurrence of ACP was highest in mature cataract followed by nuclear, lamellar, and mixed cataract. The wholemount of anterior lens epithelium revealed nonplaque and plaque region or ACP. Depending on the area, ACPs can be classified as small, medium, and large. The extracellular matrix of ACP was fibrous and amorphous. It was rich in collagen type I. The cells of the ACP were surrounded by a network of collagen type IV and were positive for alpha SMA and alpha A-crystallin. The cells of the ACP were rich in rough endoplasmic reticulum and mitochondria. CONCLUSIONS: The occurrence of ACP in pediatric eyes undergoing cataract surgery for congenital cataract was 11.5%. ACP was more associated with mature cataract. Epithelial mesenchymal transdifferentiation of lens epithelial cells may be involved in the development of congenital ACP.     

Transient activation of Notch signaling in the injured adult brain

Brain injury induces various kinds of cellular responses that lead to tissue regeneration and repair. Recent studies have demonstrated that resident progenitors proliferate and then differentiate into mature neuronal cells. We show here that proliferating cells in the cryo-injured cerebral cortex transiently expressed Notch1 immunoreactivity in their cytoplasm. Since activated Notch signaling regulates cellular fate in the developing nervous system, similar regulation may exist in the injured adult brain. To monitor the Notch signaling pathway, we examined whether components of the signaling pathway were co-expressed in Notch1-positive cells. Presenilin-1, a membrane-spanning protease that is required for the release of the Notch intracellular domain, was detected in the Notch1-positive cells and Hes1, a target of the Notch intracellular domain, also co-localized with Notch1 three days after cryo-injury. These results suggest that transient activity of the Notch signaling pathway is involved in the regulation of proliferation and differentiation of progenitors in the injured brain.     

Multidisciplinary Team-Based Palliative Care for Heart Failure and Food Intake at the End of Life

Traditionally, patients with end-stage heart failure (HF) have rarely been involved in end-of-life care (EOLC) discussions in Japan. The purpose of this study was to examine the impact of HF-specific palliative care team (HF-PCT) activities on EOLC discussions with patients, HF therapy and care, and food intake at the end of life. We retrospectively analyzed 52 consecutive patients with HF (mean age, 70 ± 15 years; 42% female) who died at our hospital between May 2013 and July 2020 and divided them into two groups: before (Era 1, n = 19) and after (Era 2, n = 33) the initiation of HF-PCT activities in June 2015. Compared to Era 1, Era 2 showed a decrease in invasive procedures, an increase in opioid and non-intubating sedative use for symptom relief, improved quality of meals at the end of life, and an increase in participation in EOLC discussions. The administration of artificial nutrition in the final three days was associated with non-ischemic cardiomyopathy etiology, the number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. HF-PCT activities may provide an opportunity to discuss EOLC with patients, reduce the burden of physical and psychological symptoms, and shift the goals of end-of-life nutritional intake to ensure comfort and quality of life.     

Localization of ADAMTS13 to the stellate cells of human liver

Although the chromosomal localization (9q34) of the gene encoding the human form of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) and its exclusive expression in the liver have been established, the cells that produce this enzyme are yet to be determined. We investigated the expression of ADAMTS13 mRNA and protein in fresh frozen specimens obtained during liver biopsies of 8 patients with liver diseases. In situ hybridizations to localize ADAMTS13 mRNA showed positive signals exclusively in perisinusoidal cells with irregularly elongated dendritic processes extending between hepatocytes. Furthermore, ADAMTS13 was detected immunohistochemically in perisinusoidal cells, whereas no staining was observed in hepatocytes. The positive cells varied in shape from unipolar to dendritic with irregularly elongated cytoplasmic processes, features common to hepatic stellate cells (HSCs). Double-labeling experiments revealed that the ADAMTS13-positive cells also expressed alpha-smooth muscle actin, confirming that these cells were activated HSCs. These results suggest that HSCs may be major cells producing ADAMTS13 in human liver.