Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain

Chronic renal fibrosis is the final common pathway of end stage renal disease caused by glomerular or tubular pathologies. Genetic background has a strong influence on the progression of chronic renal fibrosis. We recently found that Rowett black hooded rats were resistant to renal fibrosis. We aimed to investigate the role of sustained inflammation and oxidative/nitrative stress in renal fibrosis progression using this new model. Our previous data suggested the involvement of podocytes, thus we investigated renal fibrosis initiated by doxorubicin-induced (5 mg/kg) podocyte damage. Doxorubicin induced progressive glomerular sclerosis followed by increasing proteinuria and reduced bodyweight gain in fibrosis-sensitive, Charles Dawley rats during an 8-week long observation period. In comparison, the fibrosis-resistant, Rowett black hooded rats had longer survival, milder proteinuria and reduced tubular damage as assessed by neutrophil gelatinase-associated lipocalin (NGAL) excretion, reduced loss of the slit diaphragm protein, nephrin, less glomerulosclerosis, tubulointerstitial fibrosis and matrix deposition assessed by periodic acid-Schiff, Picro-Sirius-red staining and fibronectin immunostaining. Less fibrosis was associated with reduced profibrotic transforming growth factor-beta, (TGF-beta1) connective tissue growth factor (CTGF), and collagen type I alpha 1 (COL-1a1) mRNA levels. Milder inflammation demonstrated by histology was confirmed by less monocyte chemotactic protein 1 (MCP-1) mRNA. As a consequence of less inflammation, less oxidative and nitrative stress was obvious by less neutrophil cytosolic factor 1 (p47phox) and NADPH oxidase-2 (p91phox) mRNA. Reduced oxidative enzyme expression was accompanied by less lipid peroxidation as demonstrated by 4-hydroxynonenal (HNE) and less protein nitrosylation demonstrated by nitrotyrosine (NT) immunohistochemistry and quantified by Western blot. Our results demonstrate that mediators of fibrosis, inflammation and oxidative/nitrative stress were suppressed in doxorubicin nephropathy in fibrosis-resistant Rowett black hooded rats underlying the importance of these pathomechanisms in the progression of renal fibrosis initiated by glomerular podocyte damage

The Surgical Teams’ Perception of the Effects of a Routine Intraoperative Pause

BACKGROUND: A pause routine may reduce stress and errors during surgery. The aim of this study was to explore how the team, divided into the different professional groups, perceived the implementation of a pause routine and its possible impact on safety. METHODS: A pause routine was introduced at a University hospital operating theatre in Sweden in 2013. Questionnaires were distributed about 1 year later to all members of the operating theatre team. The questions included different perspectives of possible effects of the pause routine. RESULTS: A majority were positive to scheduled pauses. The surgeons often felt refreshed and at times changed their view on both anatomy and their surgical strategy. They were also perceived by other team members as improved regarding communication. All groups felt that patient safety was promoted. There were differences by profession in perception of team communication. CONCLUSIONS: The pause routine was well perceived by the surgical team. A majority believed that scheduled and regular pauses contribute to improved patient safety and better team communication. There were also findings of differences in communication and experience of team coherence between personnel categories that could benefit from further acknowledgement and exploration

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Effect of breakwater layout on waves at Puger beach Jember with Delft3D modeling

Puger Beach located in Puger Village, Jember Regency which is often passed by fishing boats to Puger Fish Market. The problem of high waves is often experienced by fishermen. In 2014, a breakwater was built in the estuary of Puger Beach to overcome the problem. However, the construction of the breakwater is considered not optimal because the layout of the building only dampens waves from the west. Based on this background, this study aims to model the sea waves that occur in the estuary of Puger Beach due to the influence of the breakwater layout. Waves were modeled based on the dominant wind direction at the study site: southwest, west, and south. Modeling was made using Delft3D software by creating five breakwater placement schemes. The modeling results obtained southwest, west, and south respectively are: the first scheme reduced the wave height by 31.01%, 27.33%, and 37%; the second scheme reduced the wave height by 28.95%, 31.59%, and 36.63%; the third scheme reduced the wave height by 78.12%, 82.08%, and 65.32%; the fourth scheme reduced the wave height by 79.91%, 47.28%, and 76.54%; the fifth scheme reduced the wave height by 94.53%, 99.78%, and 96.78%