Sural nerve sensory response in diabetic distal symmetrical polyneuropathy.

INTRODUCTION: The sural sensory nerve action potential (SNAP) amplitude is a measure of the number of axons. We tested the hypothesis that sural SNAP amplitude can be used as a marker in screening, severity evaluation, and follow-up of diabetic distal symmetrical polyneuropathy (DSPN). METHODS: Patients with type 2 diabetes underwent nerve conduction studies and were followed for 6 years. Composite amplitude scores (CASs) were determined to evaluate DSPN severity. RESULTS: Sural SNAP amplitudes were negatively correlated with CAS (r = -.790, P < .0001), and changes in sural SNAP amplitudes were negatively correlated with those of CAS after controlling for follow-up duration (r = -.531, P = .028). DISCUSSION: When a patient's baseline sural SNAP amplitude is above zero, it can be used as one measure of DSPN in screening, severity evaluation, and follow-up. However, if the patient's sural SNAP value is zero, CAS can be used as a follow-up measure.

Urinary Uromodulin/Creatinine Ratio as a Potential Clinical Biomarker for Chronic Kidney Disease Patients with Gout: A Pilot Study.

OBJECTIVE: Recent studies have reported that reduced excretion of urinary uromodulin is associated with renal tubular function and risks of progressive kidney disease. Gouty nephropathy is usually seen in patients with gout. Patients with chronic gouty nephropathy are characterized by the deposition of monosodium urate crystals primarily involving the collecting ducts in the medulla. We postulated that this correlation may be specific to gout and may serve as a useful biomarker for chronic kidney disease (CKD). MATERIALS AND METHODS: A total of 114 Taiwanese patients diagnosed with gout (n = 72), CKD (n = 26), or healthy volunteers (n = 16) were prospectively enrolled for this study from the Rheumatology and Nephrology Outpatient Clinics of our institution. We obtained urine and blood samples on patient visits to the outpatient clinics. Demographic data were obtained from medical records. RESULTS: In patients with gout, the spot urinary uromodulin/creatinine ratio (uUMCR; mg/g) in patients with CKD was significantly lower than that in those without CKD (CKD group: 2.2; non-CKD group: 5.6, p = 0.005). Multivariate analysis revealed that patients with CKD and gout had a lower uUMCR than those with gout alone (p = 0.028). A significant association was not observed in our non-gout cohort. CONCLUSION: The association of decreased uUMCR with CKD status was identified only in patients with gout in the present study. We believe that uUMCR might serve as an indicator of differential CKD in patients with gout.

Association between metabolic syndrome and bone mineral density in a Taiwanese elderly population.

Previous studies have demonstrated uncertainty regarding the effect of metabolic syndrome (MetS) on bone. In the present work, we investigated the association between MetS, its components, and decreased bone mineral density (BMD) in a cross-sectional study of patients who underwent BMD measurement by dual-energy X-ray absorptiometry during a health examination. Decreased BMD was defined as either osteopenia or osteoporosis. MetS components and body mass index (BMI) were compared between individuals with normal and decreased BMD, and simple and multivariate logistic regression analyses were used to evaluate the association between the variables and decreased BMD in women and men. Among 1162 subjects in the study, the mean age was 59.9 ± 7.3 years, and 59.5% were men. The prevalence of MetS and osteoporosis was 34.2 and 19.6%, respectively. MetS was positively associated with BMD in men, while in women it was negatively associated with BMD. Regarding the relationship between MetS components and BMD, we found that in women, waist circumference (WC) and systolic and diastolic blood pressure were negatively associated with BMD, while high-density lipoprotein cholesterol (HDL-C) was positively associated. In men, WC and fasting glucose were positively associated with BMD, while HDL-C was negatively associated. We also found that an increase in the number of MetS components resulted in a significantly increased positive association with BMD, both before and after adjusting for age, in men but not in women, revealing a gender difference in the correlation between MetS components and BMD.

Alternative Therapy for Patients With Obstructive Sleep Apnea/Hypopnea Syndrome: A 1-year, Single-blind, Randomized Trial of Tui Na.

Context • Obstructive sleep apnea/hypopnea syndrome (OSAHS) is among the most prevalent of sleep-related breathing disorders. No long-term follow-up studies have documented the continued success of lifestyle changes in treatment; oral appliances have an approximate 50% success rate; compliance with continuous positive airway pressure is poor, ranging from 50% to 89%; and the success rate of upper-airway surgery is only 66.4%. Therefore, some OSAHS patients seek alternative treatments. Objectives • The study intended to examine the efficacy of traditional Chinese therapeutic massage (tui na) for patients with OSAHS. Design • The research team designed a prospective study. Setting • The study took place at the outpatient clinic of the sleep center at the Kaohsiung Chang Gung Memorial Hospital (Kaohsiung, Taiwan), an academic tertiary medical center. Participants • Participants were 31 patients with moderate to severe OSAHS. Intervention • Each participant received a tui na treatment at multiple acupoints 2 ×/wk for 10 wk for approximately 15 min/session. Outcome Measures • At baseline and 3 mo after treatment, participants completed subjective measures, including (1) quality of life using a 36-item, short-form health survey (SF-36); (2) subjective snoring intensity indicated by bed-partners using a 0-10 visual analog scale (VAS); and (3) excessive daytime sleepiness (EDS) status, using a Chinese version of the Epworth Sleepiness Scale (CESS). The research team completed objective measures, including (1) polysomnography, (2) body mass index, and (3) neck circumference. Results • Twenty patients completed the full course of treatment. The apnea/hypopnea index per hour decreased from 43.8 ± 26.9 to 37.8 ± 31.7 after the treatments, with P = .049 (paired t test). The arousal index and rapid eye movement stage of sleep improved significantly. Statistically significant improvements were observed for the SF-36 on the score for the physical component summary, for its subscale for general health, for the mental component summary, and for 2 of its subscales: vitality and mental health. The VAS and the CESS showed that snoring intensity and EDS decreased significantly, respectively. No major complications occurred. Conclusions • Tui na is a feasible and safe treatment for patients with OSAHS. It can improve the quality of life, sleep architecture, snoring intensity, and EDS in patients with moderate-to-severe OSAHS. In the future, a controlled study should be considered to further investigate the effects of tui na for OSAHS.

Impact of Double Loading Regimen of Clopidogrel on Final Angiographic Results, Incidence of Upper Gastrointestinal Bleeding and Clinical Outcomes in Patients with STEMI Undergoing Primary Coronary Intervention.

This study tested the therapeutic impact of double-loading dose (i.e., 600 mg) versus standard-loading dose (i.e., 300 mg) of clopidogrel on ST-segment-elevation-myocardial-infarction (STEMI) patients undergoing primary-coronary-intervention (PCI).Between January 2005 and December 2013, a total of 1461 STEMI patients undergoing PCI were consecutively enrolled into the study and categorized into group 1 (600 mg/clopidogrel; n = 508) and group 2 (300 mg/clopidogrel; n = 953). We assessed angiographic thrombolysis-in-myocardial-infarction (TIMI) flow in the infarct-related-artery, 30-day mortality and upper-gastrointestinal-bleeding (UGIB) within 30 days as primary-endpoints and later incidents of UGIB as secondary-endpoints.The results showed that the incidences of advanced Killip score (defined as ≥ score 3) upon presentation (23.8% versus 24.6%) and advanced heart failure (defined as ≥ NYHAFc-3) (10.2% versus 10.4%) did not differ between groups 1 and 2 (all P > 0.4). Primary-endpoints, which were final TIM-3 flow (91.3% versus 91.7%) in the infarct-related-artery, incidences of 30-day mortality (5.8% vs. 7.1%), and UGIB ≤ 30 day (7.8% versus 8.9%) did not differ between group 1 and group 2 (all P > 0.33). The secondary-endpoints which were incidences of ≥ 30-day < one-year (5.2% versus 4.7) and > one-year (8.9% versus 10.1%) UGIB did not differ between groups 1 and 2 (all P > 0.45). One-year mortality did not differ between two groups (10.74% versus 12.9%) (P > 0.25). Multiple-stepwise-logistic-regression analysis showed that age and advanced-Killip score were independently predictive of 30-day mortality (all P < 0.001).Double-loading dose of clopidogrel did not confer an additional benefit to the final angiograph results, 30-day/one-year clinical outcomes; and age and advanced Killip-score were powerful predictors of 30-day mortality.

The cardioprotective effect of melatonin and exendin-4 treatment in a rat model of cardiorenal syndrome.

We investigated the cardioprotective effect of melatonin (Mel) and exendin-4 (Ex4) treatment in a rat model of cardiorenal syndrome (CRS). Adult male SD rats (n=48) were randomly and equally divided into sham control (SC), dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM+CKD) only, CRS-Mel (20 mg/kg/d), CRS-Ex4 (10 µg/kg/d), and CRS-Mel-Ex4 groups. In vitro results showed protein expressions of oxidative stress (NOX-1/NOX-2/oxidized protein), DNA/mitochondrial damage (γ-H2AX/cytosolic cytochrome c), apoptosis (cleaved caspase-3/PARP), and senescence (ß-galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p-cresol-treated H9c2 cells that were revised by Mel and Ex4 treatments (all P<.001). By day 60, LVEF was highest in the SC and lowest in the CRS, significantly lower in the DCM than in other treatment groups, lower in the CRS-Mel and CRS-Ex4 than in the CRS-Mel-Ex4, and lower in the CRS-Mel than in the CRS-Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P<.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS-Mel, CRS-Ex4, CRS-Mel-Ex4 to DCM (P<.0001). Protein expressions of inflammation (TNF-α/NF-κB/MMP-2/MMP-9/IL-1ß), apoptosis/DNA damage (Bax/c-caspase-3/c-PARP/γ-H2AX), fibrosis (Smad3/TGF-ß), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), cardiac hypertrophy/pressure overload (BNP/ß-MHC), and cardiac integrity (Cx43/α-MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P<.001). Fibrotic area, DNA damage (γ-H2AX+ /53BP1+ CD90+ /XRCC1+ CD90+ ), and inflammation (CD14+ /CD68+ ) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P<.001). Combined melatonin and exendin-4 treatment suppressed CRS-induced deterioration of LVEF and LV remodeling.

Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice.

AIM: Antioxidant peptide SS-31 is a class of cell-permeable small peptides, which selectively resides on the inner mitochondrial membrane and possesses intrinsic mitochondrial protective capacities. In this study we investigated the therapeutic effects of antioxidant peptide SS-31 on transverse aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in a murine model. METHODS: Adult male mice were divided into 3 groups: sham-operated mice, TAC mice, and TAC+SS-31 mice that underwent TAC surgery and received SS-31 (2 mg/d, ip) for 60 d. The right ventricular systolic blood pressure (RVSBP) was measured on d 60 prior to sacrificing the mice; then their right heart and lung tissues were collected for histological and biochemical examinations. Lung injury scores were defined by the increased crowded area and decreased number of alveolar sacs. RESULTS: TAC mice showed significantly higher RVSBP compared with sham-operated mice, the elevation was substantially suppressed in TAC+SS-31 mice. The same pattern of changes was found in pulmonary levels of oxidative stress proteins (NOX-1/NOX-2/oxidized proteins), cytosolic cytochrome c, biomarkers related to inflammation (MMP-9/TNF-α/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-ß), hypoxic (HIF-1α), DNA damage (γ-H2AX) and endothelial function (eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1(+) and HIF-1α(+) cells in pulmonary artery, and number of γ-H2AX(+) and Ki-67(+) cells in lung parenchyma. An opposite pattern of changes was observed in pulmonary anti-fibrotic markers (Smad1/5, BMP-2), number of small vessels, and number of alveolar sacs. In contrast, the levels of antioxidant proteins (HO-1/NQO-1/GR/GPx) in lung parenchyma were progressively and significantly increased from sham-operated mice, TAC mice to TAC+SS-31 mice. CONCLUSION: Antioxidant peptide SS-31 administration effectively attenuates TAC-induced PAH in mice.

Macular Diagnostic Ability in OCT for Assessing Glaucoma in High Myopia.

PURPOSE: To compare the diagnostic abilities of spectral-domain optical coherence tomography (SD-OCT; Spectralis OCT) and time-domain OCT (TD-OCT; Stratus OCT). Changes in macular parameters in highly myopic eyes of glaucoma patients and highly myopic eyes of glaucoma suspects were evaluated and compared. METHODS: We collected data from 72 highly myopic eyes (spherical equivalent, ≤-6.0D). Forty-one eyes had perimetric glaucoma and 31 eyes were suspected to have glaucoma (control group). All eyes underwent SD-OCT and TD-OCT imaging. Area under the receiver operating characteristic (AUROC) curve and sensitivity were examined on macular volume and thickness parameters at a fixed specificity and compared between groups. RESULTS: The highest TD-OCT AUROC curves were found using outer inferior sector macular thickness (AUROC curve, 0.911) and volume (AUROC curve, 0.909). The highest SD-OCT AUROC curves were found using outer inferior region thickness (AUROC curve, 0.836) and volume (AUROC curve, 0.834). The difference between the two imaging modalities was not statistically significant (thickness, p = 0.141; volume, p = 0.138). The sensitivity of TD-OCT macular outer inferior average thickness was highest and was 88.2%, with a specificity of 80.4%. The sensitivity of TD-OCT average volume measurements in this same region was 76.5%, with a specificity of 91.3%. The SD-OCT average thickness measurements also had the highest sensitivity in this region, which was 78.6%, with a specificity of 82.1%. The SD-OCT volume measurements had a sensitivity of 67.9%, with a specificity of 92.3%. CONCLUSIONS: Both SD-OCT and TD-OCT measurements of outer inferior macular thickness and volume can differentiate between eyes of glaucoma patients and glaucoma suspects with high myopia. These independent predictors all had good sensitivity. Based on our results, SD-OCT and TD-OCT have similar diagnostic abilities. These parameters may provide useful additional data in highly myopic eyes to complement standard glaucoma diagnosis tools.

Combined melatonin and exendin-4 therapy preserves renal ultrastructural integrity after ischemia-reperfusion injury in the male rat.

We tested whether combined melatonin (Mel) and exendin-4 (Ex4) treatment can better preserve glomerular structural integrity after ischemia-reperfusion (IR) injury compared with either alone. Adult male Sprague Dawley rats (n = 50) were equally divided into sham control (SC), IR, IR-Ex4 (10 µg/kg subcutaneously 30 min after reperfusion and daily for 5 days), IR-Mel (20 mg/kg intraperitoneally at 30 min postreperfusion and 50 mg/kg at 6 and 18 hr), and IR-Ex4-Mel were euthanized at day 14. Serum creatinine level and urine protein-to-creatinine ratio at days 3 and 14 were highest in IR group and lowest in SC, significantly higher in IR-Ex4 and IR-Mel groups than in IR-Ex4-Mel group (all P < 0.001) without significant difference between IR-Ex4 and IR-Mel groups. Changes in podocyte injury score (PIS) and kidney injury score were highest in IR group and lowest in SC, significantly higher in IR-Ex4 and IR-Mel groups than in IR-Ex4-Mel, and significantly higher in IR-Mel group than in IR-Ex4 group (all P < 0.001). Immunohistochemical microscopic findings of the expressions of FSP-1 and WT-1 (two glomerular damage indicators) and KIM-1 and snail (two renal tubular-damaged indicators) showed an identical pattern, whereas the expressions of ZO-1, p-cadherin, podocin, dystroglycan, fibronectin, and synaptopodin (six indices of glomerular integrity) demonstrated an opposite pattern compared to that of PIS among five groups (all P < 0.001). Protein expressions of inflammatory (TNF-α/NF-κB/MMP-9) and oxidative stress (NOX-1, NOX-2, oxidized protein) biomarkers exhibited an identical pattern to that of PIS among five groups (all P < 0.001). Combined melatonin-exednin-4 therapy further protected glomerulus from IR injury.

Protective effect of melatonin-supported adipose-derived mesenchymal stem cells against small bowel ischemia-reperfusion injury in rat.

We tested the hypothesis that combined melatonin and autologous adipose-derived mesenchymal stem cells (ADMSC) was superior to either alone against small bowel ischemia-reperfusion (SBIR) injury induced by superior mesenteric artery clamping for 30 min followed by reperfusion for 72 hr. Male adult Sprague Dawley rats (n = 50) were equally categorized into sham-operated controls SC, SBIR, SBIR-ADMSC (1.0 × 10(6) intravenous and 1.0 × 10(6) intrajejunal injection), SBIR-melatonin (intraperitoneal 20 mg/kg at 30 min after SI ischemia and 50 mg/kg at 6 and 18 hr after SI reperfusion), and SBIR-ADMSC-melatonin groups. The results demonstrated that the circulating levels of TNF-α, MPO, LyG6+ cells, CD68+ cells, WBC count, and gut permeability were highest in SBIR and lowest in SC, significantly higher in SBIR-ADMSC group and further increased in SBIR-melatonin group than in the combined therapy group (all P < 0.001). The ischemic mucosal damage score, the protein expressions of inflammation (TNF-α, NF-κB, MMP-9, MPO, and iNOS), oxidative stress (NOX-1, NOX-2, and oxidized protein), apoptosis (APAF-1, mitochondrial Bax, cleaved caspase-3 and PARP), mitochondrial damage (cytosolic cytochrome C) and DNA damage (γ-H2AX) markers, as well as cellular expressions of proliferation (PCNA), apoptosis (caspase-3, TUNEL assay), and DNA damage (γ-H2AX) showed an identical pattern, whereas mitochondrial cytochrome C exhibited an opposite pattern compared to that of inflammation among all groups (all P < 0.001). Besides, antioxidant expressions at protein (NQO-1, GR, and GPx) and cellular (HO-1) levels progressively increased from SC to the combined treatment group (all P < 0.001). In conclusion, combined melatonin-ADMSC treatment offered additive beneficial effect against SBIR injury.

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors.

AIM: Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats. METHODS: Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies. RESULTS: Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin. CONCLUSION: Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats.

BACKGROUND: We investigated whether attenuating dipeptidyl peptidase-IV (DPP4) enzyme activity protected rat heart from ischemia-reperfusion (IR) injury (40-min left anterior descending coronary artery ligation followed by 72 h reperfusion). METHODS AND RESULTS: Adult male Fischer 344 rats (n = 24) were equally divided into sham-control (WT-SC), WT-IR, and WT-IR-Sita (oral sitagliptin 400 mg/kg/day for 3 days) groups, whereas adult male DPP4-deficiency (DPP4(D)) rats (n = 16) were equally divided into DPP4(D)-SC and DPP4(D)-IR groups. Animals were sacrificed at 72 h after reperfusion with collection of heart specimens. Infarct area (H&E), collagen deposition (Sirius-red stain), fibrotic area (Masson's trichrome), and fluorescent-ROS intensity (H2DCFDA-labeling myocardium) of left ventricle were significantly higher in WT-IR than those in other groups, significantly higher in WT-IR-Sita and DPP4(D)-IR groups than in WT-SC and DPP4(D)-SC groups (all p < 0.001), but there was no difference between the latter two groups. Protein expressions of oxidative stress (oxidized protein), reactive oxygen species (NOX-1, NOX-2), inflammation (TNF-α, NF-κB, MMP-9, VCAM-1), apoptosis (mitochondrial Bax, cleaved caspase-3 and PARP), myocardial damage markers (cytosolic cytochrome-C, γ-H2AX), and number of inflammatory cells (CD14+, CD68+, CD40+ cells) showed a pattern identical to that of histological changes among all groups (all p < 0.005), whereas markers of anti-apoptosis (Bcl-2) and mitochondrial integrity (mitochondrial cytochrome-C) as well as left ventricular ejection fraction showed an opposite pattern (all p < 0.001). Protein expressions of anti-oxidants (HO-1, NQO-1), angiogenesis factors (SDF-1α, CXCR4), and glycogen-like-peptide-1-receptor were significantly higher inWT-IR-Sita and DPP4(D)-IR than those in other groups (all p <0.001). CONCLUSION: Abrogation of DPP4 activity protects against myocardial IR injury and preserved heart function.

Levels and values of lipoprotein-associated phospholipase A2, galectin-3, RhoA/ROCK, and endothelial progenitor cells in critical limb ischemia: pharmaco-therapeutic role of cilostazol and clopidogrel combination therapy.

OBJECTIVE: We tested the hypothesis that clopidogrel and cilostazol combination therapy could effectively attenuate systemic inflammatory reaction, facilitate proliferation of circulating endothelial progenitor cell (EPC), and improve the clinical outcomes of critical limb ischemia (CLI) in patients unsuitable for surgical revascularization or percutaneous transluminal angioplasty (PTA). METHODS: A total 55 patients (mean age, 72 years; 56% female) were consecutively enrolled. Clopidogrel and cilostazol combination therapy was administered throughout the study period. RESULTS: As compared with the baseline, circulating endothelial progenitor cell level (as shown by flow cytometry) was significantly increased (p<0.003), whereas the CLI-related ulcers and painfulness were significantly improved (all p<0.01) by day 90 after treatment. On the other hand, after clopidogrel and cilostazol combination therapy, galectin-3 level, lipoprotein-associated phospholipase A2 gene expression, and RhoA/ROCK-related protein expression in peripheral blood mononuclear cells were significantly suppressed (all p<0.01). Eventually, by day 90, 5 patients (9.1%) died of other etiologies, 3 (5.5%) withdrew from the study, 6 (10.9%) required amputation, and the remaining 41 had satisfactory clinical improvement with complete wound healing in 9 (16.4%) patients. CONCLUSION: The results of the present study highlight that clopidogrel and cilostazol combination therapy may be considered to be an alternative method for treating patients with CLI unsuitable for surgical revascularization or PTA.

Shockwave therapy improves anterior cruciate ligament reconstruction.

BACKGROUND: Shockwave was shown to enhance the healing of anterior cruciate ligament (ACL) reconstruction in rabbits. This study evaluated the effect of extracorporeal shockwave therapy (ESWT) on ACL reconstruction in human subjects. We hypothesized that ESWT may improve human ACL reconstruction. METHODS: Fifty-three patients were randomized into two groups with 26 patients in ESWT group and 27 patients in control group. The ESWT group underwent single-bundle hamstring autograft ACL reconstruction and received ESWT immediately after surgery. The control group underwent ACL surgery without ESWT. Both groups received the same rehabilitation postoperatively. The evaluations included Lysholm score, IKDC score and KT-1000, radiograph, bone mineral density, and magnetic resonance imaging. RESULTS: ESWT group showed significantly better Lysholm score than control group at 1 and 2 y postoperatively (P < 0.001 and 0.001, respectively). No significant difference was noted in IKDC score between the two groups (P = 0.080 and 0.076, respectively). The KT-1000 values were significantly better in ESWT group than control group at 2 y postoperatively (P = 0.027). The tibia tunnel on X-ray was significantly smaller in ESWT group compared with control group at 2 y (P = 0.018). The bone mineral density values showed no discernable difference between the two groups at 6 mo and 2 y (P = 0.522 and 0.984, respectively). On magnetic resonance imaging, ESWT group showed significant decrease in tibia tunnel enlargement at 6 mo and 2 y compared with the control group (P = 0.024 and <0.001, respectively). CONCLUSIONS: ESWT significantly improves the subjective Lysholm score and decreases the middle 1/3 tibia tunnel enlargement after single hamstring autograft ACL reconstruction.

Melatonin treatment further improves adipose-derived mesenchymal stem cell therapy for acute interstitial cystitis in rat.

This study tests the hypothesis that combined melatonin and adipose-derived mesenchymal stem cell (ADMSC, 1.2 × 10(6) given intravenously) treatment offer superior protection against cyclophosphamide (CYP 150 mg/kg)-induced acute interstitial cystitis (AIC) in rats. Male adult Sprague-Dawley rats were treated as follows: sham controls, AIC alone, AIC + melatonin, AIC + ADMSC, and AIC + melatonin +ADMSC. When melatonin was used, it was given as follows: 20 mg/kg at 30 min after CYP and 50 mg/kg at 6 and 18 hr after CYP. Twenty-four-hour urine volume, urine albumin level, and severity of hematuria were highest in AIC rats and lowest in the controls; likewise urine volume was higher in AIC + melatonin rats than in AIC + ADMSC and AIC + melatonin + ADMSC treated rats; in all cases, P < 0.001. The numbers of CD14+, CD74+, CD68+, MIP+, Cox-2+, substance P+, cells and protein expression of IL-6, IL-12, RANTES, TNF-α, NF-κB, MMP-9, iNOS (i.e. inflammatory biomarkers), glycosaminoglycan level, expression of oxidized protein, and protein expression of reactive oxygen species (NOX-1, NOX-2, NOX-4) in the bladder tissue exhibited an identical pattern compared with that of hematuria among the five groups (all P < 0.0001). The integrity of epithelial layer and area of collagen deposition displayed an opposite pattern compared to that of hematuria among all groups (P < 0.0001). The cellular expressions of antioxidants (GR, GPx, HO-1, NQO 1) showed a significant progressive increase form controls to AIC + melatonin + ADMSC (all P < 0.0001). Combined regimen of melatonin and ADMSC was superior to either alone in protecting against CYP-induced AIC.

Predictors and long-term outcome of seizures in human immuno-deficiency virus (HIV)-negative cryptococcal meningitis.

BACKGROUND: Seizures are one of the most important neurologic complications of human immuno-deficiency virus (HIV)-negative cryptococcal meningitis. A better understanding of the risk associated factors can help predict those who will require treatment. METHODS: This 22-year retrospective study enrolled 180 patients. Prognostic variables independently associated with seizures or fatality were analyzed using stepwise logistic regression. RESULTS: Twenty-eight patients with HIV-negative cryptococcal meningitis had seizures, including 13 with early seizures and 15 with late seizures. The mean time interval from HIV-negative cryptococcal meningitis to first seizure in the early and late seizure groups were 1.5 and 51.4 days, respectively. Nine out of the 28 cases (32%) occurred within 24 hours of presentation. The overall mortality rate was 54% (15/28) and two patients progressed to epilepsy. CONCLUSIONS: Patients with seizure have worse outcomes and longer hospitalization. Most first seizures occur within one year after the diagnosis of HIV-negative cryptococcal meningitis.

Prompt bone marrow-derived mesenchymal stem cell therapy enables early porcine heart function recovery from acute myocardial infarction.

Impact of early bone marrow-derived mesenchymal stem cell (BMDMSC) implantation on left ventricular (LV) function after AMI was studied.Twelve mini-pigs were equally divided into placebo (AMI through left coronary artery ligation) and cell-treated groups [BMDMSCs (3.0 × 10(7)) implanted into infarct area (IA)] with myocardium harvested by post-AMI day 90. Six healthy animals served as controls.On post-AMI day 90, magnetic resonance imaging showed a lower LV ejection fraction but higher LV dimensions in the placebo group (P < 0.003) that also had increased IAs but reduced wall thickness (P < 0.005). Pro-apoptotic gene expressions (Bax, caspase-3) and apoptotic nucleus number in IAs and peri-IAs were highest in the placebo group (P < 0.001). Inflammatory biomarker expressions (MMP-9, oxidized protein, CD40+ cells) were highest, whereas those of angiogenesis (VEGF, CD31+ cells, SDF-1α, CXCR4) and myocardium-preservation (connexin43, troponin-I, cytochrome-C) were lowest in the placebo group (P < 0.01).BMDMSC implantation preserved LV function and alleviated remodeling at post-AMI day 90.

Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction.

BACKGROUND: This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury. METHODS: Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 µm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4). RESULTS: Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-α, IL-1ß, PAI-1), protein (TNF-α, NF-κB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01). CONCLUSION: Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

Sildenafil improves long-term effect of endothelial progenitor cell-based treatment for monocrotaline-induced rat pulmonary arterial hypertension.

BACKGROUND AIMS: We hypothesized that the long-term therapeutic effect of combined sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) on monocrotaline (MCT)-induced rat pulmonary arterial hypertension (PAH) is superior to either treatment alone. METHODS: Male Sprague-Dawley rats (n = 40) were equally divided into normal controls, MCT (65 mg/kg, subcutaneously) only, MCT + sildenafil (25 mg/kg/day, orally), MCT + BMDEPCs (2.0 × 10(6) autologous cells, intravenously) and MCT + sildenafil+ BMDEPCs. BMDEPCs and sildenafil were given on day 21 after MCT administration. Animals were sacrificed by day 90 after MCT administration. RESULTS: The apoptotic (caspase 3, Bax) and inflammatory (tumor necrosis factor-α, matrix metalloproteinase-9) biomarkers in right ventricle and lung and pulmonary expressions of fibrotic biomarkers (transforming growth factor-ß, p-Smad3) and connexin 43 protein were lower in monotherapy groups (i.e., MCT + sildenafil and MCT + BMDEPCs) and further decreased in normal controls and combined treatment groups (i.e., MCT + sildenafil + BMDEPCs) compared with untreated animals (i.e., MCT only) (all P < 0.01). Expressions of anti-fibrotic biomarkers (bone morphogenetic protein-2, p-Smad1/5) and numbers of alveolar sacs and arterioles in lung were higher in monotherapy groups and further increased in normal controls and combined treatment groups compared with untreated animals (all P < 0.005). In right ventricle, connexin 43 and α-myosin heavy chain (MHC) expressions were higher in the monotherapy groups and further elevated in normal controls and combined treatment groups compared with untreated animals, whereas ß-MHC exhibited the opposite pattern (all P < 0.01). Right ventricular systolic pressure and weight were lower in the monotherapy animals and further reduced in normal controls and combined treatment groups compared with untreated animals (all P < 0.0001). CONCLUSIONS: Combined therapy with BMDEPCs and sildenafil was superior to either treatment alone in attenuating rodent MCT-induced PAH.

Innate immune response after acute myocardial infarction and pharmacomodulatory action of tacrolimus in reducing infarct size and preserving myocardial integrity.

BACKGROUND: This study investigated the association between innate immune reaction and myocardial damage after acute myocardial infarction (AMI) and anti-inflammatory role of tacrolimus in reducing infarct size. Male mini-pigs (n=18) were equally categorized into sham control (SC), untreated AMI (by ligation of left anterior descending coronary artery), and AMI-Tacrolimus (AMI-Tac) (0.5 mg intra-coronary injection 30 minutes post-AMI). Cardiac magnetic resonance imaging (MRI) was performed at post-AMI days 2, 5 and 21 before sacrificing the animals. RESULTS: By post-AMI day 21, left ventricular ejection fraction (LVEF) was lowest in untreated AMI animals, significantly higher in SC than in AMI-Tac group (all p<0.003). Infarct areas at basal, middle, and apical levels, numbers of CD14+ and iNOS+ cells in infarct area (IA) and peri-IA, and protein expression of CD14, CD68, and Ly6g from circulating inflammatory cells showed an opposite pattern compared with that of LVEF in all groups (all p<0.005). Protein expressions of MCP-1, MIP-1, TNF-α, NF-κB, iNOS, and IL-12 in IA and peri-IA exhibited an identical pattern compared to that of CD14, CD68, and Ly6g from circulating inflammatory cells (all p<0.01). Expressions of myocardial damage biomarkers in IA and peri-IA [γ-H2AX, ß-myosin heavy chain (MHC), Smad3, TGF-ß] were highest in AMI and higher in AMI-Tac than in SC, whereas expressions of myocardial integrity biomarkers (connexin43, mitochondrial cytochrome-C, α-MHC, BMP-2, Smad1/5) were opposite to those of damage biomarkers (all p<0.001). CONCLUSION: Innate immune responses were markedly augmented and LVEF was significantly reduced after AMI but were remarkably improved after tacrolimus treatment.