Chih-Chin Hsu

Aerobic interval training improves oxygen uptake efficiency by enhancing cerebral and muscular hemodynamics in patients with heart failure

BACKGROUND Abnormal ventilatory/hemodynamic responses to exercise contribute to functional impairment in patients with heart failure (HF). This study investigates how interval and continuous exercise regimens influence functional capacity by modulating ventilatory efficiency and hemodynamic function in HF patients. METHODS Forty-five HF patients were randomized to perform either aerobic interval training (AIT; 3-minute intervals at 40% and 80% VO(2peak)) or moderate continuous training (MCT; sustained 60% VO()for 30 min/day, 3 days/week for 12 weeks, or to a control group that received general healthcare (GHC). A noninvasive bio-reactance device was adopted to measure cardiac hemodynamics, whereas a near-infrared spectroscopy was employed to assess perfusion/O2 extraction in frontal cerebral lobe (∆[THb]FC/∆[HHb]FC) and vastus lateralis (∆[THb]VL/∆[HHb]VL), respectively. RESULTS Following the 12-week intervention, the AIT group exhibited higher oxygen uptake efficiency slope (OUES) and lower VE-VCO2 slope than the MCT and GHC groups. Furthermore, AIT, but not MCT, boosted cardiac output (CO) and increased ∆[THb]FC, ∆[THb]VL, and ∆[HHb]VL during exercise. In multivariate analyses, CO was the dominant predictor of VO(2peak). ∆[THb]FC and ∆[THb]VL, which modulated the correlation between CO and OUES, were significantly correlated with OUES. Simultaneously, ∆[THb]VL was the only factor significantly associated with VE-VCO2 slope. Additionally, AIT reduced plasma brain natriuretic peptide, myeloperoxidase, and interleukin-6 levels and increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score. CONCLUSIONS AIT effectively improves oxygen uptake efficiency by enhancing cerebral/muscular hemodynamics and suppresses oxidative stress/inflammation associated with cardiac dysfunction, and also promotes generic/disease-specific qualities of life in patients with HF.

Effects of Celecoxib on Migration, Proliferation and Collagen Expression of Tendon Cells

Sports-related tendinopathy is commonly treated with nonsteroidal anti-inflammatory drugs including cyclooxygenase-2 inhibitor. Tendon healing requires migration of tendon cells to the repair site, followed by proliferation and synthesis of collagen. This study was designed to determine the effects of COX-2 inhibitor (celecoxib) on the migration, proliferation, and types I and III collagen expression of tendon cells intrinsic to rat Achilles tendon. Using cultured tendon cells, cell migration and proliferation were evaluated by transwell filter migration assay and by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, respectively. The mRNA expression of α1(I) procollagen and α1(III) procollagen were determined by reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of types I and III collagen were determined by immunocytochemistry. Dose-dependent celecoxib inhibition was demonstrated for migration of tendon cells through the transwell filter migration assay (p = 0.002). Dose-dependent celecoxib inhibition of tendon cell proliferation also was demonstrated by MTT assay (p = 0.004). However, both RT-PCR and immunocytochemical staining revealed that mRNA and protein expression of types I and III collagen remained constant after celecoxib treatment. In conclusion, celecoxib inhibits tendon cell migration and proliferation. However, the expression of types I and III collagen remained unchanged.

Ibuprofen upregulates expressions of matrix metalloproteinase‐1, ‐8, ‐9, and ‐13 without affecting expressions of types I and III collagen in tendon cells

Nonsteroidal antiinflammatory drugs are widely used to treat sports‐related tendon injuries or tendinopathy. This study was designed to investigate the effect of ibuprofen on expressions of types I and III collagen, as well as collagen‐degrading enzymes including matrix metalloproteinase (MMP)‐1, ‐2, ‐8, ‐9, and ‐13. Rat Achilles tendon cells were treated with ibuprofen and then underwent MTT [3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay. Reverse transcription‐polymerase chain reaction was used to evaluate mRNA expressions of types I and III collagen, MMP‐1, ‐2, ‐8, ‐9, and ‐13. Protein expressions of types I and III collagen, MMP‐1, ‐8, and ‐13 were determined by Western blot analysis. Gelatin zymography was used to evaluate the enzymatic activities of MMP‐2 and MMP‐9. The results revealed that ibuprofen upregulated expressions of MMP‐1, ‐8, ‐9, and ‐13, both at mRNA and protein levels. There was no effect of ibuprofen on mRNA and protein expressions of types I and III collagen. Gelatin zymography revealed that the enzymatic activity of MMP‐9 was upregulated after ibuprofen treatment. In conclusion, ibuprofen upregulates the expressions of collagenases including MMP‐1, ‐8, ‐9, and ‐13 without affecting the expressions of types I and III collagen. These findings suggest a molecular mechanism potentially accounting for the inhibition of tendon healing by ibuprofen.

Effects of normoxic and hypoxic exercise regimens on cardiac, muscular, and cerebral hemodynamics suppressed by severe hypoxia in humans

Hypoxic preconditioning prevents cerebrovascular/cardiovascular disorders by increasing resistance to acute ischemic stress, but severe hypoxic exposure disturbs vascular hemodynamics. This study compared how various exercise regimens with/without hypoxia affect hemodynamics and oxygenation in cardiac, muscle, and cerebral tissues during severe hypoxic exposure. Sixty sedentary males were randomly divided into five groups. Each group (n = 12) received one of five interventions: 1) normoxic (21% O(2)) resting control, 2) hypoxic (15% O(2)) resting control, 3) normoxic exercise (50% maximum work rate under 21% O(2); N-E group), 4) hypoxic-relative exercise (50% maximal heart rate reserve under 15% O(2); H-RE group), or 5) hypoxic-absolute exercise (50% maximum work rate under 15% O(2); H-AE group) for 30 min/day, 5 days/wk, for 4 wk. A recently developed noninvasive bioreactance device was used to measure cardiac hemodynamics, and near-infrared spectroscopy was used to assess perfusion and oxygenation in the vastus lateralis (VL)/gastrocnemius (GN) muscles and frontal cerebral lobe (FC). Our results demonstrated that the H-AE group had a larger improvement in aerobic capacity compared with the N-E group. Both H-RE and H-AE ameliorated the suppression of cardiac stroke volume and the GN hyperemic response (Delta total Hb/min) and reoxygenation rate by acute 12% O(2) exposure. Simultaneously, the two hypoxic interventions enhanced perfusion (Delta total Hb) and O(2) extraction [Delta deoxyHb] of the VL muscle during the 12% O(2) exercise. Although acute 12% O(2) exercise decreased oxygenation (Delta O(2)Hb) of the FC, none of the 4-wk interventions influenced the cerebral perfusion and oxygenation during normoxic/hypoxic exercise tests. Therefore, we conclude that moderate hypoxic exercise training improves cardiopulmonary fitness and increases resistance to disturbance of cardiac hemodynamics by severe hypoxia, concurrence with enhancing O(2) delivery/utilization in skeletal muscles but not cerebral tissues.

Suppression of cerebral hemodynamics is associated with reduced functional capacity in patients with heart failure

This investigation elucidated the underlying mechanisms of functional impairments in patients with heart failure (HF) by simultaneously comparing cardiac-cerebral-muscle hemodynamic and ventilatory responses to exercise among HF patients with various functional capacities. One hundred one patients with HF [New York Heart Association HF functional class II (HF-II, n = 53) and functional class III (HF-III, n = 48) patients] and 71 normal subjects [older control (O-C, n = 39) and younger control (Y-C, n = 32) adults] performed an incremental exercise test using a bicycle ergometer. A recently developed noninvasive bioreactance device was adopted to measure cardiac hemodynamics, and near-infrared spectroscopy was employed to assess perfusions in the frontal cerebral lobe (Δ[THb](FC)) and vastus lateralis muscle (Δ[THb](VL)). The results demonstrated that the Y-C group had higher levels of cardiac output, Δ[THb](FC), and Δ[THb](VL) during exercise than the O-C group. Moreover, these cardiac/peripheral hemodynamic responses to exercise in HF-III group were smaller than those in both HF-II and O-C groups. Although the change of cardiac output caused by exercise was normalized, the amounts of blood distributed to frontal cerebral lobe and vastus lateralis muscle in the HF-III group significantly declined during exercise. The HF-III patients had lower oxygen-uptake efficiency slopes (OUES) and greater Ve-Vo(2) slopes than the HF-II patients and age-matched controls. However, neither hemodynamic nor ventilatory response to exercise differed significantly between the HF-II and O-C groups. Cardiac output, Δ[THb](FC), and Δ[THb](VL) during exercise were directly related to the OUES and Vo(2peak) and inversely related to the Ve-Vco(2) slope. Moreover, cardiac output or Δ[THb](FC) was an effect modifier, which modulated the correlation status between Δ[THb](VL) and Ve-Vco(2) slope. We concluded that the suppression of cerebral/muscle hemodynamics during exercise is associated with ventilatory abnormality, which reduces functional capacity in patients with HF.

Longitudinal followup study of ultrasonography in congenital muscular torticollis.

High-resolution ultrasonography was used to examine affected sternocleidomastoid muscles in patients with congenital muscular torticollis at different times. Thirty-one female and 42 male patients were recruited and classified as having one of four types of fibrosis based on the sonograms. Compared with initial assessment, 22 (95.6%) patients with Type I fibrosis and 22 (57.9%) patients with Type II fibrosis had a change in classification at the end of the study. Among the patients with Type I fibrosis, the classification of one patient was changed to Type III fibrosis, the classifications of two patients were changed to normal muscle, and the classifications of the other patients were changed to Type II fibrosis. For patients with Type II fibrosis, the classifications of two patients were changed to Type III fibrosis, the classifications of three patients were changed to Type IV fibrosis, and the classifications of the other patients were changed to normal muscle. No changes in classification of patients with Types III and IV fibrosis occurred during followup. Patients with Type IV fibrosis had a significantly high incidence of surgical intervention. Congenital muscular torticollis is a dynamic disease. Ultrasonography can be valuable in observing the alteration. Aggressive management may be necessary for patients with Type IV fibrosis.

Diabetic effects on microchambers and macrochambers tissue properties in human heel pads.

BACKGROUND The study attempted to highlight the differences of mechanical properties in microchambers and macrochambers between patients with type 2 diabetes mellitus and age-matched healthy volunteers. METHODS A total of 29 heels in 18 diabetic patients and 28 heels in 16 age-matched healthy participants were examined by a loading device consisting of a 10-MHz compact linear-array ultrasound transducer, a Plexiglas cylinder, and a load cell. Subjects in both groups were on average about 55 years old with a body mass index of approximately 25 kg/m(2). A stepping motor was used to progressively load the transducer on the tested heels at a velocity of 6mm/s from zero to the maximum stress of 78 kPa. Unloaded thickness, strain, and elastic modulus in microchambers, macrochambers and heel pads were measured. FINDINGS Microchambers strain in diabetic patients was significantly greater than that in healthy subjects (0.291 (SD 0.14) vs. 0.104 (SD 0.057); P<0.001). Macrochambers strain in diabetic patients was significantly less than that in healthy subjects (0.355 (SD 0.098) vs. 0.450 (SD 0.092); P=0.001). Microchambers stiffness in diabetic patients was significantly less than that in healthy persons (393 (SD 371)kPa vs. 1140 (SD 931)kPa; P<0.001). Macrochambers stiffness in diabetic patients was significantly greater than that in healthy persons (239 (SD 77)kPa vs. 181 (SD 42)kPa; P=0.001). INTERPRETATION Heel pad tissue properties are altered heterogeneously in people with diabetes. Increased macrochambers but decreased microchambers stiffness may cause diminished cushioning capacities in diabetic heels.

A regime of two intravenous injections of tranexamic acid reduces blood loss in minimally invasive total hip arthroplasty: a prospective randomised double-blind study

Tranexamic acid (TXA), an inhibitor of fibrinolysis, reduces blood loss after total knee arthroplasty. However, its effect on minimally invasive total hip arthroplasty (THA) is not clear. We performed a prospective, randomised double-blind study to evaluate the effect of two intravenous injections of TXA on blood loss in patients undergoing minimally invasive THA. In total, 60 patients (35 women and 25 men with a mean age of 58.1 years; 17 to 84) who underwent unilateral minimally invasive uncemented THA were randomly divided into the study group (30 patients, 20 women and ten men with a mean age of 56.5 years; 17 to 79) that received two intravenous injections 1 g of TXA pre- and post-operatively (TXA group), and a placebo group (30 patients, 15 women and 15 men with a mean age of 59.5 years; 23 to 84). We compared the peri-operative blood loss of the two groups. Actual blood loss was calculated from the maximum reduction in the level of haemoglobin. All patients were followed clinically for the presence of venous thromboembolism. The TXA group had a lower mean intra-operative blood loss of 441 ml (150 to 800) versus 615 ml (50 to 1580) in the placebo (p = 0.044), lower mean post-operative blood loss (285 ml (120 to 570) versus 392 ml (126 to 660) (p = 0.002), lower mean total blood loss (1070 ml (688 to 1478) versus 1337 ml (495 to 2238) (p = 0.004) and lower requirement for transfusion (p = 0.021). No patients in either group had symptoms of venous thromboembolism or wound complications. This prospective, randomised controlled study showed that a regimen of two intravenous injections of 1 g TXA is effective for blood conservation after minimally invasive THA.

Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen

Ciprofloxacin‐induced tendinopathy and tendon rupture have been previously described, principally affecting the Achilles tendon. This study was designed to investigate the effect of ciprofloxacin on expressions of matrix metalloproteinases (MMP)‐2 and ‐9, tissue inhibitors of metalloproteinase (TIMP)‐1 and ‐2 as well as type I collagen in tendon cells. Tendon cells intrinsic to rat Achilles tendon were treated with ciprofloxacin and then underwent MTT (tetrazolium) assay. Real‐time reverse‐transcription polymerase chain reaction (RT‐PCR) and Western blot analysis were used, respectively, to evaluate the gene and protein expressions of type I collagen, and MMP‐2. Gelatin zymography was used to evaluate the enzymatic activities of MMP‐2 and ‐9. Reverse zymography was used to evaluate TIMP‐1 and ‐2. Immunohistochemical staining for MMP‐2 in ciprofloxacin‐treated tendon explants was performed. Collagen degradation was evaluated by incubation of conditioned medium with collagen. The results revealed that ciprofloxacin up‐regulated the expression of MMP‐2 in tendon cells at the mRNA and protein levels. Immunohistochemistry also confirmed the increased expressions of MMP‐2 in ciprofloxacin‐treated tendon explants. The enzymatic activity of MMP‐2 was up‐regulated whereas that of MMP‐9, TIMP‐1 or TIMP‐2 was unchanged. The amount of secreted type I collagen in the conditioned medium decreased and type I collagen was degraded after ciprofloxacin treatment. In conclusion, ciprofloxacin up‐regulates the expressions of MMP‐2 in tendon cells and thus degraded type I collagen. These findings suggest a possible mechanism of ciprofloxacin‐associated tendinopathy.

Low-Level Laser Irradiation Stimulates Tenocyte Migration with Up-Regulation of Dynamin II Expression

Low-level laser therapy (LLLT) is commonly used to treat sports-related tendinopathy or tendon injury. Tendon healing requires tenocyte migration to the repair site, followed by proliferation and synthesis of the extracellular matrix. This study was designed to determine the effect of laser on tenocyte migration. Furthermore, the correlation between this effect and expression of dynamin 2, a positive regulator of cell motility, was also investigated. Tenocytes intrinsic to rat Achilles tendon were treated with low-level laser (660 nm with energy density at 1.0, 1.5, and 2.0 J/cm2). Tenocyte migration was evaluated by an in vitro wound healing model and by transwell filter migration assay. The messenger RNA (mRNA) and protein expressions of dynamin 2 were determined by reverse transcription/real-time polymerase chain reaction (real-time PCR) and Western blot analysis respectively. Immunofluorescence staining was used to evaluate the dynamin 2 expression in tenocytes. Tenocytes with or without laser irradiation was treated with dynasore, a dynamin competitor and then underwent transwell filter migration assay. In vitro wound model revealed that more tenocytes with laser irradiation migrated across the wound border to the cell-free zone. Transwell filter migration assay confirmed that tenocyte migration was enhanced dose-dependently by laser. Real-time PCR and Western-blot analysis demonstrated that mRNA and protein expressions of dynamin 2 were up-regulated by laser irradiation dose-dependently. Confocal microscopy showed that laser enhanced the expression of dynamin 2 in cytoplasm of tenocytes. The stimulation effect of laser on tenocytes migration was suppressed by dynasore. In conclusion, low-level laser irradiation stimulates tenocyte migration in a process that is mediated by up-regulation of dynamin 2, which can be suppressed by dynasore.