Association of endothelin-1 and matrix metallopeptidase-9 with metabolic syndrome in middle-aged and older adults.

BACKGROUND: Metabolic syndrome (MetS) contains a cluster of cardiovascular risk factors. People with MetS are more susceptible to cardiovascular disease, diabetes mellitus, and cancer. Endothelin-1 (ET-1) and matrix metallopeptidase-9 (MMP-9) have been implicated in the development of cardiovascular diseases, diabetes mellitus and cancers. This cross-sectional study aimed to examine the association of ET-1 and MMP-9 with MetS in middle-aged and older Hong Kong Chinese adults. METHODS: 149 adults aged 50 to 92 (n = 75 for non-MetS group and n = 74 for MetS group) were examined. All subjects were screened for MetS according to the diagnostic guideline of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Serum levels of ET-1 and MMP-9 were measured. Independent t test was used to detect differences between non-MetS and MetS groups and between subjects with or without certain metabolic abnormality. The association of the serum concentration of MMP-9 and ET-1 with MetS parameters were examined by Pearson's correlation analysis. RESULTS: Serum level of ET-1 is higher in MetS-positive subjects and in subjects with high blood pressure, elevated fasting blood glucose, and central obesity. The serum concentration of MMP-9 is higher in subjects positively diagnosed with MetS and subjects with high blood pressure, elevated fasting blood glucose, low blood high-density lipoprotein-cholesterol (HDL-C), high blood triglycerides, and central obesity. Correlation analyses revealed that serum concentration of ET-1 is positively correlated to systolic blood pressure, waist circumference, fasting blood glucose, and age whereas it is negatively correlated to HDL-C. MMP-9 is positively correlated to systolic blood pressure, waist circumference, fasting blood glucose, and age whereas it is negatively correlated to HDL-C. CONCLUSION: Serum ET-1 is higher in subjects with hypertension, hyperglycemia, central obesity or MetS. Serum MMP-9 is higher in subjects diagnosed with MetS or having either one of the MetS parameters. Both circulating levels of ET-1 and MMP-9 are correlated to systolic blood pressure, waist circumference, fasting blood glucose, HDL-C, and age. Further research is needed to fully dissect the role of ET-1 and MMP-9 in the development of cancers, diabetes and cardiovascular disease in relation to MetS.

Autophagic adaptation is associated with exercise-induced fibre-type shifting in skeletal muscle.

AIM: Acute exercise is known to activate autophagy in skeletal muscle. However, little is known about how basal autophagy in skeletal muscle adapts to chronic exercise. In the current study we aim to, firstly, examine whether long-term habitual exercise alters the basal autophagic signalling in plantaris muscle and, secondly, examine the association between autophagy and fibre-type shifting. METHODS: Adult female Sprague-Dawley rats aged 2 months were randomly assigned to control and exercise groups. Animals in exercise group were kept in cages equipped with free access running wheels to perform habitual exercise for 5 months. Animals in the control group were caged in the absence of running wheels. Animals were sacrificed after the 5-month experimental period. Plantaris muscle tissues were harvested for analysis. RESULTS: We showed that long-term habitual exercise enhanced basal autophagy, but without altering expressions of autophagy proteins in plantaris muscle. Interestingly, sirtuin protein, a possible regulator of autophagy, was upregulated in plantaris muscle. Furthermore, we suspected that different types of muscle fibre adapted to chronic exercise in different ways. Long-term habitual exercise resulted in fibre-type shifting from type IIX to IIA in both gastrocnemius muscle and plantaris muscle. Intriguingly, our analysis demonstrated that LC3-II protein abundance is positively correlated with the proportion of type IIA fibre whereas it was negatively correlated with the proportion of type IIX fibre in plantaris muscle. PGC-1α protein abundance was positively associated with the proportion of type IIA fibre and LC3-II in plantaris muscle. CONCLUSION: These results suggest that basal autophagy is enhanced in plantaris muscle after long-term habitual exercise and associated with fibre-type shifting.

Acylated and unacylated ghrelin inhibit doxorubicin-induced apoptosis in skeletal muscle.

AIM: Doxorubicin, a potent chemotherapeutic drug, has been demonstrated previously as an inducer of apoptosis in muscle cells. Extensive induction of apoptosis may cause excessive loss of muscle cells and subsequent functional decline in skeletal muscle. This study examined the effects of acylated ghrelin, a potential agent for treating cancer cachexia, on inhibiting apoptotic signalling in doxorubicin-treated skeletal muscle. Unacylated ghrelin, a form of ghrelin that does not bind to GHSR-1a, is also employed in this study to examine the GHSR-1a signalling dependency of the effects of ghrelin. METHODS: Adult C57BL/6 mice were randomly assigned to saline control (CON), doxorubicin (DOX), doxorubicin with treatment of acylated ghrelin (DOX+Acylated Ghrelin) and doxorubicin with treatment of unacylated ghrelin (DOX+Unacylated Ghrelin). Mice in all groups that involved DOX were intraperitoneally injected with 15 mg of doxorubicin per kg body weight, whereas mice in CON group received saline as placebo. Gastrocnemius muscle tissues were harvested after the experimental period for analysis. RESULTS: The elevation of apoptotic DNA fragmentation and number of TUNEL-positive nuclei were accompanied with the upregulation of Bax in muscle after exposure to doxorubicin, but all these changes were neither seen in the muscle treated with acylated ghrelin nor unacylated ghrelin after doxorubicin exposure. Protein abundances of autophagic markers including LC3 II-to-LC3 I ratio, Atg12-5 complex, Atg5 and Beclin-1 were not altered by doxorubicin but were upregulated by the treatment of either acylated or unacyated ghrelin. Histological analysis revealed that the amount of centronucleated myofibres was elevated in doxorubicin-treated muscle while muscle of others groups showed normal histology. CONCLUSIONS: Collectively, our data demonstrated that acylated ghrelin administration suppresses the doxorubicin-induced activation of apoptosis and enhances the cellular signalling of autophagy. The treatment of unacylated ghrelin has similar effects as acylated ghrelin on apoptotic and autophagic signalling, suggesting that the effects of ghrelin are probably mediated through a signalling pathway that is independent of GHSR-1a. These findings were consistent with the hypothesis that acylated ghrelin inhibits doxorubicin-induced upregulation of apoptosis in skeletal muscle while treatment of unacylated ghrelin can achieve similar effects as the treatment of acylated ghrelin. The inhibition of apoptosis and enhancement of autophagy induced by acylated and unacylated ghrelin might exert myoprotective effects on doxorubicin-induced toxicity in skeletal muscle.

Economic burden of comorbidities in patients with psoriasis is substantial.

BACKGROUND: Psoriasis is frequently associated with comorbidities. OBJECTIVE: To estimate the incremental economic burden associated with comorbidities in patients with psoriasis, accounting for psoriasis severity. METHODS: Patients continuously enrolled ≥6 months after a randomly selected psoriasis diagnosis date were selected from the Ingenix Impact National Managed Care Database (1999-2004). Comorbidities identified during the 6-month study included: psoriatic arthritis, cardiovascular disease, depression, diabetes, hyperlipidemia, hypertension, obesity, cerebrovascular diseases and peripheral vascular disease. Resource utilization and costs during the 6-month follow-up period were compared for patients with ≥1 comorbidity vs. those without and for patients with a specific comorbidity vs. those without. Adjusted incidence rate ratios (IRRs) and odds ratios (ORs) were estimated for resource utilization using negative binomial and logistic regression models, respectively. Adjusted incremental costs associated with comorbidities were reported using general linear models with log-link and gamma distributions or two-part models. Models controlled for age, sex and psoriasis severity. RESULTS: A total of 114,512 patients were included; 51% had ≥1 comorbidity. Hyperlipidemia (27%) and hypertension (25%) were most prevalent. Patients with comorbidities were more likely to experience urgent care [OR (95% confidence interval (CI))=1.58 (1.51-1.65)] than patients without comorbidities. They also had significantly greater hospitalization rates [IRR (95% CI)=2.27 (2.13-2.42)] and outpatient visits [IRR (95% CI)=1.53 (1.52-1.55)]. Compared with patients who did not have comorbidities, patients with comorbidities incurred $2184 (P<0.001) greater total costs. CONCLUSION: Comorbidities present a significant economic burden in patients with psoriasis.

The benefits of timely intervention with zoledronic acid in patients with metastatic prostate cancer to bones: a retrospective study of the US Veterans Affairs population.

To examine the effect of timely zoledronic acid (ZA) treatment on clinical outcomes and health care utilization in patients with bone-metastatic prostate cancer. Patients with prostate cancer and bone metastasis were identified in a Veterans Affairs database (01/2002-09/2009). Eligible patients had no documented skeletal-related events (SREs) before the index date (that is, the first bone metastasis diagnosis date). Patients who received early ZA treatment, defined as having a ZA infusion after the index date and before any recorded SREs, were matched 1:1 on propensity score to patients not treated with bisphosphonates (BPs). Risks of SREs, hospitalization and death during the 6-month post-index period were compared between matched cohorts using Kaplan-Meier analyses. Baseline characteristics were well balanced between the matched cohorts (n = 73 per group). 6-month SRE-free survival and hospitalization-free survival were higher in patients receiving timely ZA than patients without BP treatment (91.7 versus 71.5%, P < 0.01; 80.5 versus 66.3%, P = 0.05, respectively). 6-month mortality risk was significantly lower in patients treated with ZA versus those without BP treatment (4.3 versus 13.8%, P = 0.04). Timely ZA intervention in bone-metastatic prostate cancer patients was associated with significant reductions in 6-month risks of SREs, hospitalization and mortality, as compared with no BP treatment.

The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy.

BACKGROUND: Adalimumab induces and maintains remission in adults with Crohn's disease. AIM: To evaluate safety, fistula healing, quality of life and work productivity in adalimumab-treated patients who failed infliximab, including primary nonresponders. METHODS: After a ≥8-week infliximab washout, patients with moderate-to-severe Crohn's disease received open-label adalimumab as induction (160/80 mg at weeks 0/2) and maintenance (40 mg every other week) therapies. At/after 8 weeks, patients with flare/nonresponse could receive weekly therapy. Minimum study duration was 8 weeks, continuing until the commercial availability of adalimumab for Crohn's disease. RESULTS: Of 673 patients enrolled, 17% were infliximab primary nonresponders and 83% were initial responders. Three percent of patients had serious infections (mainly abscesses). Complete fistula healing was achieved by 34/88 (39%) patients with baseline fistulas. Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients, as well as the subgroup of primary nonresponders. CONCLUSIONS: Blinded clinical trials have shown adalimumab to be both an effective first-line therapy for anti-TNF-naïve patients and an important treatment option for infliximab-refractory or -intolerant patients. This trial presents open-label experience to support further the safety and effectiveness of adalimumab in patients who failed infliximab therapy, including primary nonresponders (NCT00338650).

Economic impact of switching from valsartan to other angiotensin receptor blockers in patients with hypertension.

BACKGROUND: The approaching availability of lower-cost generic angiotensin receptor blockers (ARBs) may affect formulary policies for patients maintained on the ARB valsartan. OBJECTIVE: Estimate the economic impact of switching from valsartan (including valsartan-based single-pill combinations) to other ARBs without apparent medical reasons. RESEARCH DESIGN AND METHODS: Patients with essential hypertension and at least 6 months of continuous valsartan treatment free of hospitalization, cardiovascular events, renal events or ARB-associated adverse events were identified from the MarketScan administrative claims database from January 1, 2004 to March 31, 2008. Those who subsequently switched to a different ARB with at least a 5% copayment decrease (switchers) were matched to those who did not switch (maintainers) according to propensity score quintiles and selected baseline characteristics. Refills were not required after the index fill for the switched-to ARB or maintained valsartan. Matched switchers and maintainers were compared in terms of medication discontinuation, healthcare resource use and costs during the 6 months following the index fill. RESULTS: A total of 99,926 valsartan maintainers and 2150 switchers (with a mean copayment decrease of $16.5 per month) were identified and matched. After matching, switching from versus maintaining valsartan was associated with an 8% higher risk of medication discontinuation (p < 0.008), 19.1 additional outpatient visits/100 patients (p = 0.002) and 9.3 additional hypertension-related inpatient days/100 patients (p = 0.030). Concurrently, switching from versus maintaining valsartan was associated with higher total medical costs by $748/patient (p < 0.001), driven largely by higher costs for hypertension-related medical services by $492/patient (p = 0.004). LIMITATIONS: Exact reasons for switching were not available and the study assessed only the short-term impacts of switching. CONCLUSIONS: Hypertension patients maintained on valsartan who switched to a different ARB with a lower copayment experienced substantial increases in medication discontinuation, healthcare resource use and costs compared to those who maintained valsartan treatment.

Systematic review: the costs of ulcerative colitis in Western countries.

BACKGROUND: Early onset and complications such as hospitalization and surgery contribute to the economic burden of ulcerative colitis. AIM: To review systematically the literature on costs of ulcerative colitis in Western countries. METHODS: Studies estimating costs of ulcerative colitis in Western countries were identified using Medline, EMBASE and ISI Web of Science and were rated based on relevance and reliability of estimates. All costs were adjusted to 2008 currency values. A parallel review focused on the impact of disease severity on costs, hospitalizations and surgeries. RESULTS: Estimated annual per-patient direct medical costs of ulcerative colitis ranged from $6217 to $11,477 in the United States and from euro8949 to euro10,395 in Europe. Hospitalizations accounted for 41-55% of direct medical costs. Indirect costs accounted for approximately one-third of total costs in the United States and 54-68% in Europe. Total economic burden of ulcerative colitis was estimated at $8.1-14.9 billion annually in the United States and at euro12.5-29.1 billion in Europe; total direct costs were $3.4-8.6 billion in the United States and euro5.4-12.6 billion in Europe. Direct costs, hospitalizations and surgeries increased with worsening disease severity. CONCLUSIONS: Ulcerative colitis is a costly disease. Hospitalizations contribute significantly to direct medical costs, and indirect costs are considerable, having previously been substantially underestimated.

Asthma severity categorization using a claims-based algorithm or pulmonary function testing.

OBJECTIVES: This study was performed to determine whether pulmonary function test results would appreciably alter asthma severity categorization determined by an algorithm using information readily available in administrative databases. METHODS: Patients 6 to 64 years of age with asthma diagnosed from 1999-2005, who had at least one pulmonary function test, were identified from a claims database of a medical group practice located in central Massachusetts. Asthma severity for these patients was categorized using information available in an administrative database (claims-based algorithm) and by percent predicted forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow (PEF) abstracted from medical charts (pulmonary function test method). Gamma rank correlation index was used to measure the association between the two severity categorization methods. Total and asthma-related healthcare costs for each severity category were compared between the two different approaches. RESULTS: There was a significant ordinal association between severity categorization with the two classification approaches (p = 0.0002). The pulmonary function test method resulted in more frequent mild categorizations and less frequent moderate and severe categorizations than the claims-based algorithm. In only 10.9% of patients did the pulmonary function test method result in a more severe asthma category than the claims-based algorithm. Patients with more severe asthma, determined by both methods, had higher total and asthma-related health care costs. Total and asthma-related health care costs were similar for each asthma severity categorization for the two classification approaches, except for asthma-related costs in the moderate severity categories. CONCLUSION: The claims-based algorithm generally categorized patients as having more severe asthma than the approach using pulmonary function test results. Pulmonary function test results would have appreciably changed asthma severity categorization in only a small percent of patients. These findings add further support to the use of administrative database analyses for the evaluation of asthma care in large populations.

Are sex differences in child motor activity level a function of sex differences in maturational status?

By virtue of being farther along a developmental path for motor activity level, girls may appear to be the less active sex when compared to less physically mature but same-aged boys. If so, observed sex differences in activity level may be an epiphenomenon of sex differences in maturity related declines in AL. To test this hypothesis and the associated premise that females would be more mature and less active than males, the customary activity levels and relative physical maturities of 83 5-8-year-olds were assessed. Relative maturity (percentage of estimated adult height attained) was negatively related to activity level, and girls were both less motorically active and more mature than boys. Though reduced in magnitude, the sex effect remained significant after maturity was added as a predictor of AL. Thus, sex differences are not due only to maturity differences but may be partially mediated by them.