The effect of age and calorie restriction on HIF-1-responsive genes in aged liver

Hypoxia inducible factor-1 (HIF-1) regulates transactivation of several genes in response to hypoxia condition. We explore hepatic HIF-1 responsive gene regulation during aging and the age-related changes of the HIF-1 related gene activation in young and old rats. Results indicate that the aging process induces the activation of HIF-1, which is accompanied by increased HIF-1 DNA binding. This increased binding activity is accompanied by the increase of HIF-1-dependent genes, heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), erythropoietin (EPO), and inducible nitric oxide synthase (iNOS), which all showed remarkable up-regulation during aging process. In contrast, the increased HIF-1 related gene expression was effectively blunted by the anti-oxidative action of calorie restriction in aged rat liver. We propose that age-related HIF-1 binding activity may well be influenced by the increased pro-oxidative conditions of aged animals, which up-regulate HIF-1-dependent gene expression.Min Ju Kang and Hyon Jeen Kim Contributed equally to this work     

Laparoscopic vs. Hand-Assisted Laparoscopic Sigmoidectomy for Diverticulitis

Introduction Sigmoid colectomy for diverticulitis can be technically challenging because of severe inflammation in the left-lower quadrant and pelvis. We hypothesized that hand-assisted laparoscopic technique may facilitate laparoscopic completion of this surgery while retaining the short-term benefits associated with “pure” laparoscopic surgery, in which an incision is made only for extracting the specimen. This study was designed to compare the outcomes of patients who underwent totally laparoscopic or hand-assisted laparoscopic sigmoidectomy for diverticulitis. Methods We reviewed our prospectively collected patient database from July 2001 to June 2004 and compared the intraoperative data and postoperative outcomes of patients who underwent elective laparoscopic or hand-assisted laparoscopic sigmoidectomies for diverticulitis. Complicated patients (with abscess or fistulas) also were separately analyzed. Results The hand-assisted laparoscopic (mode age, 57 years; 48 percent male) and laparoscopic sigmoidectomy (mode age, 56 years; 90 percent male) groups were similar with regard to age and gender. Overall, patients who underwent laparoscopic (n = 21) vs. hand-assisted laparoscopic (n = 21) sigmoidectomies had a significantly longer operative time (197 ± 42 vs. 171 ± 34 minutes, P = 0.04) and shorter incision length (5 ± 2.1 vs. 9.3 ± 4.1 cm, P = 0.0001). Patients with complicated diverticulitis (n = 14; abscess, colovesical fistula, enterocolic fistula) who underwent laparoscopic sigmoidectomies (n=4) had a significantly longer operative time compared with hand-assisted laparoscopic sigmoidectomy (n = 10) group (255 ± 18 vs. 177 ± 34 minutes, P = 0.001). Conversion rate for the laparoscopic group was significantly higher (3/4 vs. 1/10, P = 0.04, Fisher exact) when complicated diverticulitis was present. There were no differences in postoperative outcomes or incision lengths in thecomplicated group. Conclusions Outcomes after hand-assisted laparoscopic sigmoidectomy for diverticulitis are similar to those seen in the pure laparoscopic method, with lower conversion rates and shorter operative times. Hand-assisted laparoscopic sigmoid resection for diverticulitis is an attractive alternative to a “pure” laparoscopic method in complicated cases. Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, April 30 to May 5, 2005. Reprints are not available.     

The use of thermal treatments to enhance the mechanical properties of electrospun poly(epsilon-caprolactone) scaffolds

Nonwoven nanofiber scaffolds fabricated by electrospinning technology have been widely used for tissue engineering applications. Although electrospun nanofiber scaffolds fulfill many requirements for tissue engineering applications, they sometimes lack the necessary biomechanical properties. To attempt to improve the biomechanical properties of electrospun poly(epsilon-caprolactone) (PCL) scaffolds, fibers were bonded by thermal treatment. The thermal fiber bonding was performed in Pluronic F127 solution at a range of temperatures from 54 degrees C to 60 degrees C. Thermally bonded electrospun PCL scaffolds were characterized by analyzing the changes in morphology, fiber diameter, pore area, tensile properties, suture retention strength, burst pressure strength, and compliance. The biomechanical properties of the thermally bonded electrospun PCL scaffolds were significantly increased without any gross observable and ultrastructural changes when compared to untreated PCL scaffolds. This study suggests that the introduction of thermal fiber bonding to electrospun PCL scaffolds improved the biomechanical properties of these scaffolds, making them more suitable for tissue engineering applications.     

Quantum-dot-assisted fluorescence resonance energy transfer approach for intracellular trafficking of chitosan/DNA complex

Fluorescence resonance energy transfer (FRET) was employed to monitor the molecular dissociation of a chitosan/DNA complex with different molecular weights of chitosan. Chitosan with different molecular weights was complexed with plasmid DNA and the complex formation was monitored using dynamic light scattering and a gel retardation assay. As the chitosan molecular weight increased, a more condensed complex was prepared at various ratios of chitosan to DNA. Plasmid DNA and chitosan were separately labeled with quantum dots and Texas red, respectively, and the dissociation of the complex was subsequently monitored using confocal microscopy and fluorescence spectroscopy. As the chitosan molecular weight in the chitosan/DNA complex increased, the Texas red-labeled chitosan gradually lost FRET-induced fluorescence light when HEK293 cells incubated with chitosan/DNA complex were examined with confocal microscopy. This suggests that the dissociation of the chitosan/DNA complex was more significant in the high molecular weight chitosan/DNA complex. Fluorescence spectroscopy also monitored the molecular dissociation of the chitosan/DNA complex at pH 7.4 and pH 5.0 and confirmed that the dissociation occurred in acidic environments. This finding suggests that the high molecular weight chitosan/DNA complex could easily be dissociated in lysosomes compared to a low molecular weight complex. Furthermore, the high molecular weight chitosan/DNA complex showed superior transfection efficiency in relation to the low molecular weight complex. Therefore, it could be concluded that the dissociation of the chitosan/DNA complex is a critical event in obtaining the high transfection efficiency of the gene carrier/DNA complex.     

A randomized,open-label study comparing low-dose clevudine plus adefovir combination therapy with clevudine monotherapy in naïve chronic hepatitis B patients

Purpose

Clevudine 30 mg showed potent antiviral activity with a marked post-treatment antiviral effect. However, long-term treatment with clevudine monotherapy induced resistance and myopathy in some cases. The objective of this study is to evaluate the preliminary efficacy and safety of the combination of clevudine 20 mg and adefovir compared to clevudine monotherapy.

Methods

Seventy-four patients were randomized to either a combination of clevudine 20 mg and adefovir or clevudine 20 or 30 mg and were treated for 2 years. The viral kinetics for 24 weeks, virological response [VR; hepatitis B virus (HBV) DNA less than 300 copies/ml], and the biochemical response [BR; normal alanine aminotransferase (ALT)] were assessed.

Results

There was no difference in baseline characteristics among the three groups. Viral kinetics study showed no statistically significant difference among them during 24 weeks. The combination group showed 95 % virological response with a statistically significant difference compared to the clevudine 30 mg (67 %) and 20 mg (71 %) groups (p = 0.0376). Biochemical response rates were similar in all groups (78–94 %). No resistance was reported in the combination group, while 20 % of patients treated with clevudine 30 mg or 20 mg reported resistance during 2 years. Muscle-related symptoms such as myalgia (1 in clevudine 30 mg, 1 in the combination group) and muscle weakness (1 in clevudine 30 mg, 2 in clevudine 20 mg) were reported in five patients (7 %); of these, three patients discontinued the study.

Conclusion

We concluded that the combination of clevudine 20 mg and adefovir produced a potent antiviral response together with a good resistance profile compared to clevudine monotherapy at 96 weeks in this pilot study.     

Role of induction and consolidation chemotherapy in elderly acute myeloid leukemia patients

The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P < 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG <2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P < 0.001) and poor performance status (ECOG >2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P < 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and >1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.     

Process control analysis of IMRT QA: implications for clinical trials

The purpose of this study is two-fold: first is to investigate the process of IMRT QA using control charts and second is to compare control chart limits to limits calculated using the standard deviation (sigma). Head and neck and prostate IMRT QA cases from seven institutions in both academic and community settings are considered. The percent difference between the point dose measurement in phantom and the corresponding result from the treatment planning system (TPS) is used for analysis. The average of the percent difference calculations defines the accuracy of the process and is called the process target. This represents the degree to which the process meets the clinical goal of 0% difference between the measurements and TPS. IMRT QA process ability defines the ability of the process to meet clinical specifications (e.g. 5% difference between the measurement and TPS). The process ability is defined in two ways: (1) the half-width of the control chart limits, and (2) the half-width of +/-3sigma limits. Process performance is characterized as being in one of four possible states that describes the stability of the process and its ability to meet clinical specifications. For the head and neck cases, the average process target across institutions was 0.3% (range: -1.5% to 2.9%). The average process ability using control chart limits was 7.2% (range: 5.3% to 9.8%) compared to 6.7% (range: 5.3% to 8.2%) using standard deviation limits. For the prostate cases, the average process target across the institutions was 0.2% (range: -1.8% to 1.4%). The average process ability using control chart limits was 4.4% (range: 1.3% to 9.4%) compared to 5.3% (range: 2.3% to 9.8%) using standard deviation limits. Using the standard deviation to characterize IMRT QA process performance resulted in processes being preferentially placed in one of the four states. This is in contrast to using control charts for process characterization where the IMRT QA processes were spread over three of the four states with none of the processes in the ideal state. Control charts may be used for IMRT QA in clinical trials to categorize process performance, minimize protocol variation and guide process improvements. For the duration of an institution's participation in a protocol, updated control charts can be periodically sent to the protocol QA center to document continued process performance to protocol specifications.     

Association of metabolically abnormal but normal weight (MANW) and metabolically healthy but obese (MHO) individuals with arterial stiffness and carotid atherosclerosis

Objective

Despite recent interest in differential impact of body size phenotypes on cardiovascular outcomes and mortality, studies evaluating the association between body size phenotypes and indicators of atherosclerosis are limited. This study investigated the relationship of metabolically abnormal but normal weight (MANW) and metabolically healthy but obese (MHO) individuals with arterial stiffness and carotid atherosclerosis in Korean adults without cardiovascular disease.

Methods

A total of 1012 participants (575 men and 437 women, mean age 50.8 years), who underwent a health examination between April 2012 and May 2013 were prospectively enrolled based on inclusion and exclusion criteria. Study subjects were classified according to body mass index (BMI) and the presence/absence of metabolic syndrome.

Results

The prevalence of metabolically healthy normal weight (MHNW), MANW, MHO, and metabolically abnormal obese (MAO) were 54.84%, 6.42%, 22.83%, and 15.91%, respectively. Individuals with MANW had significantly higher brachial-ankle pulse wave velocity and maximal carotid intima-media thickness values than those with MHO, after adjusting for age and gender (P = 0.026 and P = 0.018, respectively). The odds ratio (OR) of arterial stiffness and carotid atherosclerosis in the MANW group were significantly higher than in the MHNW group in unadjusted models. Furthermore, multivariable models showed that increased OR of carotid atherosclerosis in the MANW group persisted even after adjusting for confounding factors (OR = 2.98, 95% CI = [1.54, 5.73], P = 0.011).

Conclusions

Compared to MHNW or MHO subjects, Korean men and women with the MANW phenotype exhibited increased arterial stiffness and carotid atherosclerosis.

Clinical trials no

NCT01594710.     

Mineralocorticoid and glucocorticoid receptor expressions in astrocytes and microglia in the gerbil hippocampal CA1 region after ischemic insult

In the present study, we observed expression and changes of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the gerbil hippocampal CA1 region, but not in the CA2/3 region, after 5 min of transient forebrain ischemia. In blood, corticosterone levels were increased biphasically at 30 min and 12 h after ischemia/reperfusion, and thereafter its levels were decreased. In the sham-operated group, MR and GR immunoreactivities were weakly detected in the CA1 region. By 3 days after ischemia, MR and GR were not significantly altered in the CA1 region: at 12 h after ischemia, GR was expressed in a few neurons in the CA1 region, whereas MR was not expressed in any neurons after ischemic insult. From 4 days after ischemia, MR and GR immunoreactivities were detected in astrocytes and microglia in the CA1 region, and at 7 days after ischemia, MR and GR immunoreactivities peaked in the hippocampal CA1 region. At this time, 55% of astrocytes and 30% of microglia showed MR immunoreactivity, and 20% of astrocytes and 40% of microglia showed GR immunoreactivity. Western blot analyses showed that the pattern of changes in MR and GR protein levels was similar to the immunohistochemical changes observed after transient forebrain ischemia. From 4 days after ischemia, MR and GR protein levels were increased time-dependently after ischemia. In conclusion, enhanced MR and GR expressions in astrocytes and microglia were detected in the hippocampal CA1 region 4-7 days after ischemia/reperfusion. At this time, GR immunoreactivity was abundant in microglia, whereas MR immunoreactivity was prominent in astrocytes. The specific distribution of corticosteroid receptors in the astrocytes and microglia may be associated with the differences of MR and GR functions against ischemic damage.     

Seroprevalence of hepatitis B virus among health care workers in Korea

We studied the seroprevalence of HBsAg, anti-HBs and anti-HBc and the vaccination histories among health care workers (HCWs) at a large suburban referral hospital in Korea. The purpose of this study was to determine the immune status of HCWs against hepatitis B virus and we also wanted to prepare a practical guideline to protect HCWs from occupational exposure. During December, 2003, 571 HCWs (56 physicians, 289 nurses, 113 technicians and 113 aid-nurses) aged between 21 and 74 yr were included in the surveillance. The positive rates of HBsAg and anti-HBs were 2.4% (14/571) and 76.9% (439/571), respectively. The positive rate of anti-HBs was lower in the physician group, and this was associated with the male gender and older age. Of the 439 anti-HBs positive cases, 320 cases (73.1%) were anti-HBc negative and this was significantly associated with a past history of HBV vaccination. The distribution of the anti-HBs levels was not associated with age (except for HCWs in their sixties), gender or occupation. Our study revealed that the seroprevalence rates of HBsAg and anti-HBs in HCWs in Korea were not different from those of the general population. Based on this surveillance, we can make reasonable decisions in case of occupational exposure to hepatitis B virus.