Dynamics of Lamin-A Processing Following Precursor Accumulation

Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed

Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the combination of a rapid intravenous infusion of cold saline and endovascular hypothermia in a closed chest pig infarct model.</p> <p>Methods</p> <p>Pigs were randomized to pre-reperfusion hypothermia (n = 7), post-reperfusion hypothermia (n = 7) or normothermia (n = 5). A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min. Hypothermia was started after 25 min of ischemia or immediately after reperfusion by infusion of 1000 ml of 4°C saline and endovascular hypothermia. Area at risk was evaluated by in vivo SPECT. Infarct size was evaluated by ex vivo MRI.</p> <p>Results</p> <p>Pre-reperfusion hypothermia reduced infarct size/area at risk by 43% (46 ± 8%) compared to post-reperfusion hypothermia (80 ± 6%, p < 0.05) and by 39% compared to normothermia (75 ± 5%, p < 0.05). Pre-reperfusion hypothermia infarctions were patchier in appearance with scattered islands of viable myocardium. Pre-reperfusion hypothermia abolished (0%, p < 0.001), and post-reperfusion hypothermia significantly reduced microvascular obstruction (10.3 ± 5%; p < 0.05), compared to normothermia: (30.2 ± 5%).</p> <p>Conclusion</p> <p>Rapid hypothermia with cold saline and endovascular cooling before reperfusion reduces myocardial infarct size and microvascular obstruction. A novel finding is that hypothermia at the onset of reperfusion reduces microvascular obstruction without reducing myocardial infarct size. Intravenous administration of cold saline combined with endovascular hypothermia provides a method for a rapid induction of hypothermia suggesting a potential clinical application.</p

Incidence and mortality of hip fracture among the elderly population in South Korea: a population-based study using the National Health Insurance claims data

<p>Abstract</p> <p>Background</p> <p>The lack of epidemiologic information on osteoporotic hip fractures hampers the development of preventive or curative measures against osteoporosis in South Korea. We conducted a population-based study to estimate the annual incidence of hip fractures. Also, we examined factors associated with post-fracture mortality among Korean elderly to evaluate the impact of osteoporosis on our society and to identify high-risk populations.</p> <p>Methods</p> <p>The Korean National Health Insurance (NHI) claims database was used to identify the incidence of hip fractures, defined as patients having a claim record with a diagnosis of hip fracture and a hip fracture-related operation during 2003. The 6-month period prior to 2003 was set as a 'window period,' such that patients were defined as incident cases only if their first record of fracture was observed after the window period. Cox's proportional hazards model was used to investigate the relationship between survival time and baseline patient and provider characteristics available from the NHI data.</p> <p>Results</p> <p>The age-standardized annual incidence rate of hip fractures requiring operation over 50 years of age was 146.38 per 100,000 women and 61.72 per 100,000 men, yielding a female to male ratio of 2.37. The 1-year mortality was 16.55%, which is 2.85 times higher than the mortality rate for the general population (5.8%) in this age group. The risk of post-fracture mortality at one year is significantly higher for males and for persons having lower socioeconomic status, living in places other than the capital city, not taking anti-osteoporosis pharmacologic therapy following fracture, or receiving fracture-associated operations from more advanced hospitals such as general or tertiary hospitals.</p> <p>Conclusion</p> <p>This national epidemiological study will help raise awareness of osteoporotic hip fractures among the elderly population and hopefully motivate public health policy makers to develop effective national prevention strategies against osteoporosis to prevent hip fractures.</p

Mild hypothermia reduces cardiac post-ischemic reactive hyperemia

BACKGROUND: In experimentally induced myocardial infarction, mild hypothermia (33–35°C) is beneficial if applied prior to ischemia or reperfusion. Hypothermia, when applied after reperfusion seems to confer little or no benefit. The mechanism by which hypothermia exerts its cell-protective effect during cardiac ischemia remains unclear. It has been hypothesized that hypothermia reduces the reperfusion damage; the additional damage incurred upon the myocardium during reperfusion. Reperfusion results in a massive increase in blood flow, reactive hyperemia, which may contribute to reperfusion damage. We postulated that hypothermia could attenuate the post-ischemic reactive hyperemia. METHODS: Sixteen 25–30 kg pigs, in a closed chest model, were anesthetized and temperature was established in all pigs at 37°C using an intravascular cooling catheter. The 16 pigs were then randomized to hypothermia (34°C) or control (37°C). The left main coronary artery was then catheterized with a PCI guiding catheter. A Doppler flow wire was placed in the mid part of the LAD and a PCI balloon was then positioned proximal to the Doppler wire but distal to the first diagonal branch. The LAD was then occluded for ten minutes in all pigs. Coronary blood flow was measured before, during and after ischemia/reperfusion. RESULTS: The peak flow seen during post-ischemic reactive hyperemia (during the first minutes of reperfusion) was significantly reduced by 43 % (p < 0.01) in hypothermic pigs compared to controls. CONCLUSION: Mild hypothermia significantly reduces post-ischemic hyperemia in a closed chest pig model. The reduction of reactive hyperemia during reperfusion may have an impact on cardiac reperfusion injury

Clinical performance and radiation dosimetry of no-carrier-added vs carrier-added 123I-metaiodobenzylguanidine (MIBG) for the assessment of cardiac sympathetic nerve activity

Purpose We hypothesized that assessment of myocardial sympathetic activity with no-carrier-added (nca) I-123-metaiodobenzylguanidine (MIBG) compared to carrier-added (ca) I-123-MIBG would lead to an improvement of clinical performance without major differences in radiation dosimetry. Methods In nine healthy volunteers, 15 min and 4 h planar thoracic scintigrams and conjugate whole-body scans were performed up to 48 h following intravenous injection of 185 MBq I-123-MIBG. The subjects were given both nca and ca I-123-MIBG. Early heart/mediastinal ratios (H/M), late H/M ratios and myocardial washout were calculated. The fraction of administered activity in ten source organs was quantified from the attenuation-corrected geometric mean counts in conjugate views. Radiation-absorbed doses were estimated with OLINDA/EXM software. Results Both early and late H/M were higher for nca I-123-MIBG (ca I-123-MIBG early H/M 2.46 +/- 0.15 vs nca I-123-MIBG 2.84 +/- 0.15, p = 0.001 and ca I-123-MIBG late H/M 2.69 +/- 0.14 vs nca I-123-MIBG 3.34 +/- 0.18, p = 0.002). Myocardial washout showed a longer retention time for nca I-123-MIBG (p <0.001). The effective dose equivalent (adult male model) for nca I-123-MIBG was similar to that for ca I-123-MIBG (0.025 +/- 0.002 mSv/MBq vs 0.026 +/- 0.002 mSv/MBq, p = 0.055, respectively). Conclusion No-carrier-added I-123-MIBG yields a higher relative myocardial uptake and is associated with a higher myocardial retention. This difference between nca I-123-MIBG and ca I-123-MIBG in myocardial uptake did not result in major differences in estimated absorbed doses. Therefore, nca I-123-MIBG is to be preferred over ca I-123-MIBG for the assessment of cardiac sympathetic activit

Developmental Transcriptomic Features of the Carcinogenic Liver Fluke, Clonorchis sinensis

Clonorchis sinensis is the causative agent of the life-threatening disease endemic to China, Korea, and Vietnam. It is estimated that about 15 million people are infected with this fluke. C. sinensis provokes inflammation, epithelial hyperplasia, and periductal fibrosis in bile ducts, and may cause cholangiocarcinoma in chronically infected individuals. Accumulation of a large amount of biological information about the adult stage of this liver fluke in recent years has advanced our understanding of the pathological interplay between this parasite and its hosts. However, no developmental gene expression profiles of C. sinensis have been published. In this study, we generated gene expression profiles of three developmental stages of C. sinensis by analyzing expressed sequence tags (ESTs). Complementary DNA libraries were constructed from the adult, metacercaria, and egg developmental stages of C. sinensis. A total of 52,745 ESTs were generated and assembled into 12,830 C. sinensis assembled EST sequences, and then these assemblies were further categorized into groups according to biological functions and developmental stages. Most of the genes that were differentially expressed in the different stages were consistent with the biological and physical features of the particular developmental stage; high energy metabolism, motility and reproduction genes were differentially expressed in adults, minimal metabolism and final host adaptation genes were differentially expressed in metacercariae, and embryonic genes were differentially expressed in eggs. The higher expression of glucose transporters, proteases, and antioxidant enzymes in the adults accounts for active uptake of nutrients and defense against host immune attacks. The types of ion channels present in C. sinensis are consistent with its parasitic nature and phylogenetic placement in the tree of life. We anticipate that the transcriptomic information on essential regulators of development, bile chemotaxis, and physico-metabolic pathways in C. sinensis that presented in this study will guide further studies to identify novel drug targets and diagnostic antigens