QT Interval and Long‐Term Mortality Risk in the Framingham Heart Study

Background : The association between QT interval and mortality has been demonstrated in large, prospective population‐based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT‐mortality relationship in the Framingham Heart Study (FHS). Methods : Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a reproducible digital caliper technique. Results : Using Cox proportional hazards regression adjusting for age and sex, a 20 millisecond increase in QTc (using Bazett's correction; QT/RR^1/2 interval) was associated with a modest increase in risk of all‐cause mortality (HR 1.14, 95% CI 1.10–1.18, P < 0.0001), coronary heart disease (CHD) mortality (HR 1.15, 95% CI 1.05–1.26, P = 0.003), and sudden cardiac death (SCD, HR 1.19, 95% CI 1.03–1.37, P = 0.02). However, adjustment for heart rate using RR interval in linear regression attenuated this association. The association of QT interval with all‐cause mortality persisted after adjustment for cardiovascular risk factors, but associations with CHD mortality and SCD were no longer significant. Conclusion : In FHS, there is evidence of a graded relation between QTc and all‐cause mortality, CHD death, and SCD; however, this association is attenuated by adjustment for RR interval. These data confirm that using Bazett's heart rate correction, QTc, overestimates the association with mortality. An association with all‐cause mortality persists despite a more complete adjustment for heart rate and known cardiovascular risk factors.     

Hyperbaric oxygen treatment prevents nitric oxide‐induced apoptosis in articular cartilage injury via enhancement of the expression of heat shock protein 70

Heat shock proteins (HSPs), inflammatory cytokines, nitric oxide (NO), and localized hypoxia‐induced apoptosis are thought to be correlated to the degree of cartilage injury. We investigated the effect of hyperbaric oxygen (HBO) on (1) interleukin‐1β (IL‐1β)‐induced NO production and apoptosis of rabbit chondrocytes and (2) healing of articular cartilage defects. For the in vitro study, RT‐PCR and Western blotting were performed to detect mRNA and protein expressions of HSP70, inducible NO synthase (iNOS), and caspase 3 in IL‐1β‐treated chondrocytes. To clarify that the HSP70 was necessary for anti‐iNOS and anti‐apoptotic activity by HBO, we treated the cells with an HSP70 inhibitor, KNK437. For the in vivo study, cartilage defects were created in rabbits. The HBO group was exposed to 100% oxygen at 2.5 ATA for 1.5 h a day for 10 weeks. The control group was exposed to normal air. After sacrifice, specimen sections were sent for examination using a scoring system. Immunohistochemical analyses were performed to detect the expressions of iNOS, HSP70, and caspase 3. Our results suggested that HBO upregulated the mRNA and protein expressions of HSP70 and suppressed those of iNOS and caspase 3 in chondrocytes. KNK437 inhibited the HBO‐induced downregulation of iNOS and casapase 3 activities. The histological scores showed that HBO markedly enhanced cartilage repair. Immunohistostaining showed that HBO enhanced HSP70 expression and suppressed iNOS and caspase 3 expressions in chondrocytes. Accordingly, HBO treatment prevents NO‐induced apoptosis in articular cartilage injury via enhancement of the expression of heat shock protein 70. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 376–384, 2013     

Damage and the repeated bout effect of arm,leg, and trunk muscles induced by eccentric resistance exercises

This study compared nine resistance eccentric exercises targeting arm, leg, and trunk muscles in one session for changes in maximal voluntary isometric contraction strength (MVC), delayed onset muscle soreness (DOMS), plasma creatine kinase (CK) activity, and myoglobin (Mb) concentration after the first and second bouts. Fifteen sedentary men (20‐25 years) performed 5 sets of 10 eccentric contractions with 80% of MVC load for the elbow flexors (EF), elbow extensors (EE), pectoralis, knee extensors (KE), knee flexors (KF), plantar flexors (PF), latissimus, abdominis, and erector spinae (ES) in a randomized order and repeated the same exercises 2 weeks later. MVC decreased at 1 (16%‐57%) to 4 (13%‐49%) days, DOMS developed (peak: 43‐70 mm), and CK activity (peak: 23 238‐207 304 IU/L) and Mb concentration showed large increases after the first bout. The magnitude of decrease in MVC was greater (P < 0.05) for EF, EE, and PEC than others and for KF than KE, PF, and ES. DOMS was greater (P < 0.05) for EF, EE, and ES than others. Changes in all measures were smaller (P < 0.05) after the second than the first bout, and the magnitude of the repeated bout effect was similar among the muscles. Plasma CK activity and Mb concentration did not increase significantly after the second exercise bout. It was concluded that muscle damage was greater for arm than leg muscles, and muscle proteins in the blood increased to a critical level after unaccustomed whole‐body resistance exercises, but the magnitude of damage was largely attenuated for all muscles similarly after the second bout.     

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)‐molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and five compounds that were analogous to a known inhibitor with an available crystal structure. TI‐MD simulations of the first two compounds (analogs 1 and 2 ) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results. The rest three compounds (analogs 3 – 5 ) were newly obtained from a database search, and their affinity data were newly measured in our labs. TI‐MD simulations predicted the binding modes and the computed ΔΔG values have a reasonably good correlation with the experimental affinity data. These newly identified inhibitors appear to be new leads according to our survey of GSK3β inhibitors listed in recent review articles. The predicted binding modes of these compounds should aid in designing new derivatives of these compounds in the future.     

Effect of radial shock wave therapy for carpal tunnel syndrome: A prospective randomized,double‐blind,placebo‐controlled trial

Three recent studies demonstrated the positive effect of extracorporeal shock wave therapy (ESWT) for treating carpal tunnel syndrome (CTS). However, none have entirely proved the effects of ESWT on CTS because all studies had a small sample size and lacked a placebo‐controlled design. Moreover, radial ESWT (rESWT) has not been used to treat CTS. We conducted a prospective randomized, controlled, double‐blinded study to assess the effect of rESWT for treating CTS. Thirty‐four enrolled patients (40 wrists) were randomized into intervention and control groups (20 wrists in each). Participants in the intervention group underwent three sessions of rESWT with nightly splinting, whereas those in the control group underwent sham rESWT with nightly splinting. The primary outcome was visual analog scale (VAS), whereas the secondary outcomes included the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ), cross‐sectional area (CSA) of the median nerve, sensory nerve conduction velocity of the median nerve, and finger pinch strength. Evaluations were performed before treatment and at 1, 4, 8, and 12 weeks after the third rESWT session. A significantly greater improvement in the VAS, BCTQ scores, and CSA of the median nerve was noted in the intervention group throughout the study as compared to the control group (except for BCTQ severity at week 12 and CSA at weeks 1 and 4) (p < 0.05). This is the first study to assess rESWT in a randomized placebo‐controlled trial and demonstrate that rESWT is a safe and effective method for relieving pain and disability in patients with CTS. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:977–984, 2016.