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1.  Melatonin augments apoptotic adipose-derived mesenchymal stem cell treatment against sepsis-induced acute lung injury 
This study investigated whether combining melatonin and apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) was superior to ADMSC alone in ameliorating sepsis-induced acute lung injury. Adult male Sprague-Dawley rats (n=50) were randomized equally into five groups: sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP-melatonin-A-ADMSC. Circulating interleukin (IL)-6 at 6, 18, and 72 hrs, were highest in CLP and lowest in SC groups, higher in CLP-melatonin than CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, higher in CLP-A-ADMSC than CLP-melatonin-A-ADMSC groups (all p<0.001). Immune reactivity (indicated by circulating cytotoxic-, and regulatory-T cells) and WBC count at 72 h exhibited the same pattern as that of circulating IL-6 (all p<0.001). Changes in histological scoring of lung parenchyma and the number of CD68+ and CD14+ cells showed a similar pattern compared to that of IL-6 level in all groups (all p<0.001). Changes in protein expressions of inflammatory (oxidative stress, RANTES, TNF-α, NF-κB, MMP-9, MIP-1, IL-1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-β) markers and those of reactive-oxygen-species (NOX-1, NOX-2) displayed an identical pattern compared to that of circulating IL-6 in all groups (all p<0.001). Anti-oxidative capacities (GR+, GPx+, HO-1, NQO-1+) and angiogenesis marker (CXCR4+ cells) were lowest in SC group but highest in CLP-melatonin-A-ADMSC group, lower in CLP than CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin than CLP-A-ADMSC groups (all p<0.001). In conclusion, combined melatonin and A-ADMSC were superior to A-ADMSC alone in protecting the lung from sepsis-induced injury.
PMCID: PMC4212921  PMID: 25360211
Sepsis-induced organ injury; inflammation; oxidative stress; reactive oxygen species; adipose-derived mesenchymal stem cells; and melatonin
2.  Revision of the Taiwanese millipede genus Chamberlinius Wang, 1956, with descriptions of two new species and a reclassification of the tribe Chamberlinini (Diplopoda, Polydesmida, Paradoxosomatidae, Paradoxosomatinae)  
ZooKeys  2011;1-27.
The millipede genus Chamberlinius is basically confined to Taiwan, with only one of the four known species presumably introduced to southern Japan. Both previously known species are redescribed, based on new material: Chamberlinius hualienensis Wang, 1956 (the type species) and Chamberlinius piceofasciatus (Gressitt, 1941), the latter being a new subjective senior synonym of Chamberlinius shengmui Wang, 1957, syn. n. Two further congeners are described as new: Chamberlinius pessior sp. n. and Chamberlinius sublaevus sp. n. The genus is re-diagnosed, all of its four species are keyed, and their distributions mapped. The tribe Chamberlinini is reclassified and, based on gonopod traits, shown to comprise the following five genera: Chamberlinius Wang, 1956, Haplogonosoma Brölemann, 1916, Riukiupeltis Verhoeff, 1939, Aponedyopus Verhoeff, 1939 and Geniculodesmus Chen, Golovatch and Chang, 2008.
PMCID: PMC3095131  PMID: 21594069
Millipede; Chamberlinius; Chamberlinini; taxonomy; new species; key; distribution; Taiwan
3.  The millipede family Polydesmidae in Taiwan, with descriptions of five new species (Polydesmida, Diplopoda)  
ZooKeys  2011;9-42.
Polydesmidae are represented in Taiwan by seven species in two genera. Neither of the genera is endemic to Taiwan, but six of the species are, including five new: Nipponesmus minor sp. n., Epanerchodus bispinosus sp. n., Epanerchodus curtigonopus sp. n., Epanerchodus flagellifer sp. n. and Epanerchodus pinguis sp. n. In addition, the diagnosis of the hitherto enigmatic genus Nipponesmus Chamberlin & Wang, 1953 is refined vis-à-vis the especially similar, Central Asian, Siberian and Eastern European genus Schizoturanius Verhoeff, 1931, chiefly based on new material of the type-species Nipponesmus shirinensis Chamberlin & Wang, 1953; this species is adequately redescribed and represents still another Taiwanese endemic. A key to all three currently known species of Nipponesmus Chamberlin & Wang, 1953 is given. The highly speciose Central to East Asian genus Epanerchodus Attems, 1901 is represented in Taiwan by five species, all keyed, including Epanerchodus orientalis Attems, 1901, which is long known to be highly variable in Japan and found particularly polymorphous and apparently allochthonous in Taiwan. The following synonymy is formalized: Epanerchodus orientalis orientalis Attems, 1901 = Epanerchodus orientalis takakuwai Verhoeff, 1913, syn. n. The genus Usbekodesmus Lohmander, 1932 is formally synonymized with Epanerchodus Attems, 1901, syn. n., resulting in the following new formal transfers: Epanerchodus redikorzevi (Lohmander, 1932), Epanerchodus swatensis (Golovatch, 1991), Epanerchodus varius (Geoffroy & Golovatch, 2004), Epanerchodus anachoretus (Golovatch, 1986), Epanerchodus buddhis (Golovatch, 1986), Epanerchodus occultus (Golovatch, 1986), Epanerchodus sacer (Golovatch, 1987), Epanerchodus theocraticus (Golovatch, 1990) and Epanerchodus theosophicus (Golovatch, 1986), all comb. n. ex Usbekodesmus. The distributions of all seven species of Polydesmidae occurring in Taiwan are mapped and discussed.
PMCID: PMC3095181  PMID: 21594077
millipede; Polydesmidae; taxonomy; new species; new synonymy; key; Taiwan
4.  Revision of the endemic Taiwanese millipede genus Aponedyopus Verhoeff, 1939, with descriptions of two new species (Diplopoda, Polydesmida, Paradoxosomatidae). Advances in the systematica of Diplopoda III 
ZooKeys  2010;1-21.
The millipede genus Aponedyopus is endemic to Taiwan and contains three species. All previously described nominal species are considered to represent one species: Aponedyopus montanus Verhoeff, 1939 (the type species), including Aponedyopus reesi (Wang, 1957) and Aponedyopus maculatus Takakuwa, 1942, syn. n. Two further species are described as new: Aponedyopus similis sp. n. and Aponedyopus latilobatus sp. n. The genus is re-diagnosed, all of its three species are keyed, and their distributions mapped.
PMCID: PMC3083003  PMID: 21594102
Millipede; Aponedyopus; taxonomy; new species; distribution; key; Taiwan
5.  Clinical features and predictive factors of intraventricular rupture in patients who have bacterial brain abscesses 
Intraventricular rupture of brain abscesses (IVRBA) remains a catastrophic and fatal complication of bacterial brain abscess (BBA). However, no information has been reported about the risk factors that are predictive of intraventricular rupture.
This study was undertaken to determine the potential risk factors that are predictive of intraventricular ruptures in patients with BBA but without intraventricular rupture when arriving at the hospital. A comparison is also made between patients who already have IVRBA at the time of admission (initial IVRBA) and those who have the episode during hospitalisation (subsequent IVRBA).
62 patients, including 45 who had initial IVRBA and 17 who had subsequent IVRBA, were examined. Stepwise logistic regression analysis showed that the adjusted risk of intraventricular rupture during hospitalisation for patients with multiloculated brain abscesses had an odds ratio (OR) of 4.2 (95% confidence interval (CI) 1.24 to 14.3; p = 0.02) compared with those without multiloculated brain abscesses (referent); a reduction of 1 mm in the distance between the ventricle and brain abscesses would increase the rupture rate by 10% (p = 0.006, OR 0.9, 95% CI 0.83 to 0.97).
This study shows that if the abscess is deep seated, multiloculated and close to the ventricle wall, a reduction of 1 mm in the distance between the ventricle and brain abscesses will increase the rupture rate by 10%. Despite aggressive medical and surgical management shown in this series, many patients continue to progress poorly.
PMCID: PMC2117635  PMID: 17012340
6.  Apoptotic adipose-derived mesenchymal stem cell therapy protects against lung and kidney injury in sepsis syndrome caused by cecal ligation puncture in rats 
We tested the hypothesis that apoptotic adipose-derived mesenchymal stem cells (A-ADMSC) are superior to healthy (H)-ADMSC in attenuating cecal ligation puncture (CLP)-induced sepsis-mediated lung and kidney injuries.
Adult male rats divided into group 1 (sham controls), group 2 (CLP), group 3 [CLP + H-ADMSC administered at 0.5, 6, and 18 hours after CLP], and group 4 [CLP + A-ADMSC administered as in group 3] were sacrificed 72 hours after CLP with blood, lung, and kidney collected for studies.
White blood cell (WBC) count, circulating TNF-α and creatinine levels were higher in groups 2 and 3 than in groups 1 and 4 (all P < 0.001). Kidney and lung damage scores were highest in group 2, lowest in group 1, significantly higher in group 3 than in group 4 (all P < 0.0001). Protein expressions of inflammatory (ICAM-1, MMP-9, TNF-α, NF-κB), oxidative, and apoptotic (Bax, caspase-3, PARP) biomarkers were higher in groups 2 and 3 than groups 1 and 4, whereas anti-apoptotic (Bcl-2) and mitochondrial integrity (cytochrome-C) biomarkers were lower in groups 2 and 3 than in groups 1 and 4 (all P < 0.001). Expressions of anti-oxidant biomarkers at protein (GR, GPx, NQO-1, HO-1) and cellular (GR, GPx) levels were highest in group 4 (all P < 0.001). The number of inflammatory cells (CD3+) in lungs and levels of DNA damage marker (γ-H2AX) in kidneys were higher in groups 2 and 3 than in groups 1 and 4 (all P < 0.001).
A-ADMSC therapy was superior to H-ADMSC therapy in protecting major organs from damage in rats with CLP-induced sepsis syndrome.
PMCID: PMC4054966  PMID: 24451364
7.  Reducing TRPC1 Expression through Liposome-Mediated siRNA Delivery Markedly Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension in a Murine Model 
Stem Cells International  2014;2014:316214.
We tested the hypothesis that Lipofectamine siRNA delivery to deplete transient receptor potential cation channel (TRPC) 1 protein expression can suppress hypoxia-induced pulmonary arterial hypertension (PAH) in mice. Adult male C57BL/6 mice were equally divided into group 1 (normal controls), group 2 (hypoxia), and group 3 (hypoxia + siRNA TRPC1). By day 28, right ventricular systolic pressure (RVSP), number of muscularized arteries, right ventricle (RV), and lung weights were increased in group 2 than in group 1 and reduced in group 3 compared with group 2. Pulmonary crowded score showed similar pattern, whereas number of alveolar sacs exhibited an opposite pattern compared to that of RVSP in all groups. Protein expressions of TRPCs, HIF-1α, Ku-70, apoptosis, and fibrosis and pulmonary mRNA expressions of inflammatory markers were similar pattern, whereas protein expressions of antifibrosis and VEGF were opposite to the pattern of RVSP. Cellular markers of pulmonary DNA damage, repair, and smooth muscle proliferation exhibited a pattern similar to that of RVSP. The mRNA expressions of proapoptotic and hypertrophy biomarkers displayed a similar pattern, whereas sarcomere length showed an opposite pattern compared to that of RVSP in all groups. Lipofectamine siRNA delivery effectively reduced TRPC1 expression, thereby attenuating PAH-associated RV and pulmonary arteriolar remodeling.
PMCID: PMC4281407  PMID: 25587286
8.  Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats 
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 (DPP4D) rats (n = 16) were equally divided into DPP4D-SC and DPP4D-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 DPP4D-IR groups than in WT-SC and DPP4D-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 DPP4D-IR than those in other groups (all p < 0.001).
Abrogation of DPP4 activity protects against myocardial IR injury and preserved heart function.
PMCID: PMC4301397  PMID: 25496837
Ischemia-reperfusion injury; Dipeptidyl peptidase-IV (DPP4) enzyme; Sitagliptin; Inflammation; Oxidative stress; Heart function
9.  Extracorporeal shock wave therapy ameliorates cyclophosphamide-induced rat acute interstitial cystitis though inhibiting inflammation and oxidative stress-in vitro and in vivo experiment studies 
Background: We investigated whether extracorporeal shock wave (ECSW) therapy can attenuate cyclophosphamide (CYP)-induced acute interstitial cystitis (AIC) in rats. Methods and Results: Eighteen male-adult Sprague-Dawley rats were equally divided into group 1 (sham control), group 2 (AIC induced by 150 mg/kg CYP by intra-peritoneal injection) and group 3 (AIC + ECSW 200 impulses at 0.11 mJ/mm2 to the urinary bladder at 3 and 24 h after CYP treatment). Smooth-muscle cells co-culture with menadione (25 µM) with and without ECSW treatment was performed. Western-blot results demonstrated that ECSW significant attenuated oxidative stress and inflammatory reactions in this in-vitro studies (all p < 0.001). 24-hour urine amount and microscopic findings of red-blood-cell count (i.e., hematuria) were higher in group 2 than in groups 1 and 3, and significantly higher in group 3 than in group 1 (all p < 0.001). The urine levels of albumin and interleukin-6 showed an identical pattern of hematuria among all three groups (all p < 0.001). The cellular and mRNA expressions of macrophage migration inhibitory factor (MIF)+, CD74+, CD68+, substance p+, and Cox-2+ cells in the bladder tissue exhibited an identical pattern of hematuria among all groups (all p < 0.0001). The integrity of epithelial layer and collagen-deposition area as stained by Sirius red displayed an opposite pattern of hematuria among the three groups (p < 0.0001). The protein expression of IL-12, iNOS, TNF-α, NF-κB, MMP-9, NOX-1, NOX-2, RANTES, and Oxyblot displayed an identical pattern of hematuria among all groups (all p < 0.01). Conclusion: ECSW therapy markedly attenuated CYP-induced AIC through inhibitions of the inflammation and oxidative stress.
PMCID: PMC4297333  PMID: 25628776
Acute interstitial cystitis; cyclophosphamide treatment; extra-corporeal shock wave; inflammatory biomarkers
10.  Predictors and long-term outcome of seizures in human immuno-deficiency virus (HIV)-negative cryptococcal meningitis 
BMC Neurology  2014;14(1):208.
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.
This 22-year retrospective study enrolled 180 patients. Prognostic variables independently associated with seizures or fatality were analyzed using stepwise logistic regression.
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.
Patients with seizure have worse outcomes and longer hospitalization. Most first seizures occur within one year after the diagnosis of HIV-negative cryptococcal meningitis.
PMCID: PMC4203868  PMID: 25307800
Outcome; Risk factors; Seizures; HIV-negative cryptococcal meningitis
11.  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 
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).
A total 55 patients (mean age, 72 years; 56% female) were consecutively enrolled. Clopidogrel and cilostazol combination therapy was administered throughout the study period.
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.
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.
PMCID: PMC4234320  PMID: 24742198
Critical limb ischemia; Endothelial progenitor cells; Inflammation; Clopidogrel; Cilostazol therapy
12.  Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma 
Vascular abnormalities are the predominant histologic changes associated with radiation in nasopharyngeal carcinoma (NPC). This study examined if the duration after radiotherapy correlates with the progression of carotid intima-media thickness (IMT) and investigated its relationship with inflammatory markers.
One hundred and five NPC patients post-radiotherapy for more than one year and 25 healthy control subjects were examined by B-mode ultrasound for IMT measurement at the far wall of the common carotid artery (CCA). Surrogate markers including lipid profile, HbA1c, and high sensitive C-reactive protein (hs-CRP) were assessed.
The IMT of CCA was significantly increased in NPC patients and carotid plaque was detected in 38 NPC patients (38/105, 36.2%). Significant risk factors for carotid plaques included age, duration after radiotherapy, and HbA1c levels. Age, duration after radiotherapy, hs-CRP, HbA1c, and platelet count positively correlated with IMT. The cut-off value of age and duration after radiotherapy for the presence of plaque was 52.5 years and 42.5 months, respectively. In NPC subjects, multiple linear regression analysis revealed that age, gender, duration after radiotherapy and platelet counts were independently associated with CCA IMT. After adjustments for age, gender and platelet counts, IMT increased in a linear manner with duration after radiotherapy.
Radiation-induced vasculopathy is a dynamic and progressive process due to late radiation effects. Extra-cranial color-coded duplex sonography can be part of routine follow-up in NPC patients aged ≥50 years at 40 months post-radiotherapy.
PMCID: PMC3827874  PMID: 24196030
Atherosclerosis; Nasopharyngeal carcinoma; Radiotherapy; Risk factors
13.  Innate immune response after acute myocardial infarction and pharmacomodulatory action of tacrolimus in reducing infarct size and preserving myocardial integrity 
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.
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, β-myosin heavy chain (MHC), Smad3, TGF-β] 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).
Innate immune responses were markedly augmented and LVEF was significantly reduced after AMI but were remarkably improved after tacrolimus treatment.
PMCID: PMC4174893  PMID: 24165293
14.  Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction 
This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.
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).
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-1β, 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).
Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.
PMCID: PMC4231365  PMID: 24161164
Exendin-4; Sitagliptin; Acute ischemia-reperfusion injury; Inflammation; Oxidative stress
15.  High Duty Cycle to Low Duty Cycle: Echolocation Behaviour of the Hipposiderid Bat Coelops frithii 
PLoS ONE  2013;8(5):e62938.
Laryngeally echolocating bats avoid self-deafening (forward masking) by separating pulse and echo either in time using low duty cycle (LDC) echolocation, or in frequency using high duty cycle (HDC) echolocation. HDC echolocators are specialized to detect fluttering targets in cluttered environments. HDC echolocation is found only in the families Rhinolophidae and Hipposideridae in the Old World and in the New World mormoopid, Pteronotus parnellii. Here we report that the hipposiderid Coelops frithii, ostensibly an HDC bat, consistently uses an LDC echolocation strategy whether roosting, flying, or approaching a fluttering target rotating at 50 to 80 Hz. We recorded the echolocation calls of free-flying C. frithii in the field in various situations, including presenting bats with a mechanical fluttering target. The echolocation calls of C. frithii consisted of an initial narrowband component (0.5±0.3 ms, 90.6±2.0 kHz) followed immediately by a frequency modulated (FM) sweep (194 to 113 kHz). This species emitted echolocation calls at duty cycles averaging 7.7±2.8% (n = 87 sequences). Coelops frithii approached fluttering targets more frequently than did LDC bats (C.frithii, approach frequency  = 40.4%, n = 80; Myotis spp., approach frequency  = 0%, n = 13), and at the same frequency as sympatrically feeding HDC species (Hipposideros armiger, approach rate  = 53.3%, n = 15; Rhinolophus monoceros, approach rate  = 56.7%, n = 97). We propose that the LDC echolocation strategy used by C. frithii is derived from HDC ancestors, that this species adjusts the harmonic contents of its echolocation calls, and that it may use both the narrowband component and the FM sweep of echolocations calls to detect fluttering targets.
PMCID: PMC3663840  PMID: 23717396
16.  Paradoxical impairment of angiogenesis, endothelial function and circulating number of endothelial progenitor cells in DPP4-deficient rat after critical limb ischemia 
We hypothesized that dipeptidyl peptidase-IV (DPP4) may impair angiogenesis, endothelial function, and the circulating number of endothelial progenitor cells (EPC) in a model of critical limb ischemia (CLI) through ligating the left femoral artery using DPP4-deficient rats.
Adult male DPP4-deficient (DPP4D) rats (n = 18) were equally divided into CLI only (DPP4D-CLI) and CLI treated by granulocyte colony-stimulating factor (GCSF) (DPP4D-CLI-GCSF). For comparison, age-matched wild-type (WT) Fischer 344 rats (n = 18) were randomized into two groups receiving identical treatment compared to their DPP4-deficient counterparts and labeled as WT-CLI (n = 9) and WT-CLI-GCSF (n = 9), respectively.
The circulating number of EPCs (CD31+, CD34+, CD133, C-kit+) was significantly lower in DPP4-deficient than in WT rats on post-CLI days 1 and 4 (all P < 0.01). The ratio of ischemia/normal blood flow was remarkably lower in DPP4D-CLI-GCSF rats than in WT-CLI-GCSF animals on post-CLI Day 14 (all P < 0.01). Protein expressions of pro-angiogenic factors (endothelial nitric oxide synthase (eNOS), CXCR4, SDF-1α, vascular endothelial growth factor (VEGF)) were remarkably higher in WT-CLI than in DPP4D-CLI rats, and higher in WT-CLI-GCSF than in DPP4D-CLI-GCSF animals (all P < 0.01). Moreover, the numbers of small vessel in the ischemic area were substantially higher in WT-CLI-GCSF than in DPP4D-CLI-GCSF rats (P < 0.001). Furthermore, vasorelaxation and nitric oxide production of the normal femoral artery were significantly reduced in DPP4-deficient than in WT Fischer rats (all P < 0.01).
Contrary to our hypothesis, DPP4-deficient rats were inferior to age-matched WT Fischer rats in terms of angiogenesis, endothelial function, circulating EPC number and response to GCSF, suggesting a positive role of DPP4 in maintaining vascular function and tissue perfusion in this experimental setting.
PMCID: PMC3706813  PMID: 23517567
17.  Bacterial brain abscess in patients with nasopharyngeal carcinoma following radiotherapy: microbiology, clinical features and therapeutic outcomes 
BMC Infectious Diseases  2012;12:204.
This study aimed to analyze the clinical features, causative pathogens, neuro-imaging findings, and therapeutic outcomes of bacterial brain abscess in patients with nasopharyngeal carcinoma (NPC) following radiotherapy.
NPC patients with bacterial brain abscess were evaluated. Their clinical data were collected over a 22-year period. For comparison, the clinical features, causative pathogens, neuro-imaging findings, and therapeutic outcomes between NPC and non-NPC patients were analyzed.
NPC accounted for 5.7% (12/210) of the predisposing factors, with Viridans streptococci and Staphylococcus aureus as the two most common causative pathogens. Significant statistical analysis between the two groups (NPC and non-NPC patients) included chronic otitis media (COM) as the underlying disease, post-radiation necrosis by neuro-imaging, and the temporal lobe as the most common site of brain abscesses. The fatality rate in patients with and without NPC was 16.7% and 20.7%, respectively.
NPC patients with bacterial brain abscess frequently have COM as the underlying disease. Neuro-imaging often reveals both post-radiation necrosis and the temporal lobe as the most common site of brain abscesses, the diagnosis of which is not always a straightforward process. Radiation necrosis can mimic brain abscess on neuro-imaging and pose significant diagnostic challenges. Early diagnosis and treatment is essential for survival.
PMCID: PMC3482557  PMID: 22943134
Bacterial brain abscess; Nasopharyngeal carcinoma; Therapeutic outcome
18.  Combination of cilostazol and clopidogrel attenuates Rat critical limb ischemia 
Background and aim
Procedural failure and untoward clinical outcomes after surgery remain problematic in critical limb ischemia (CLI) patients. This study tested a clopidogrel-cilostazol combination treatment compared with either treatment alone in attenuating CLI and improving CLI-region blood flow in rats.
Male Sprague–Dawley rats (n = 40) were equally divided into five groups: control, CLI induction only, CL I + cilostazol (12.0 mg/day/kg), CLI + clopidogrel (8.0 mg/kg/day) and CLI + combined cilostazol-clopidogrel. After treatment for 21 days, Laser Doppler imaging was performed.
On day 21, the untreated CLI group had the lowest ratio of ischemic/normal blood flow (p < 0.001). Inflammation measured by VCAM-1 protein expression; oxidative stress; PAI-1, MMP-9 and TNF-α mRNA expressions; and immunofluorescence staining (IF) of CD68+ cells was lower with combined treatment than with the other treatments, and lower in the two single-treatment groups than the untreated CLI group (all p < 0.01). Anti-inflammatory mRNA expression of interleukin-10, and eNOS showed a reverse pattern among these groups. Apoptosis measured by Bax, caspase-3 and PARP; and muscle damage measured by cytosolic cytochrome-C, and serum and muscle micro-RNA-206 were all lowest with combination treatment, and the two single-treatment groups showed lower values than the untreated group (all p < 0.001). Angiogenesis measured by eNOS, IF staining of CD31+ and vWF + cells; and number of vessels in CLI region were highest with combination treatment and higher in the single-treatment groups than the untreated group (all p < 0.001).
Combined cilostazol-clopidogrel therapy is superior to either agent alone in improving ischemia in rodent CLI.
PMCID: PMC3479044  PMID: 22897925
Critical limb ischemia; Apoptosis; Inflammation; Pharmacomodulation; Angiogenesis
19.  Levels and values of circulating endothelial progenitor cells, soluble angiogenic factors, and mononuclear cell apoptosis in liver cirrhosis patients 
The roles of circulating endothelial progenitor cell (EPC) and mononuclear cell apoptosis (MCA) in liver cirrhosis (LC) patients are unknown. Moreover, vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α are powerful endogenous substances enhancing EPC migration into circulation. We assessed the level and function of EPCs [CD31/CD34 (E1), KDR/CD34 (E2), CXCR4/CD34 (E3)], levels of MCA, VEGF and SDF-1α in circulation of LC patients.
Blood sample was prospectively collected once for assessing EPC level and function, MCA, and plasma levels of VEGF and SDF-1α using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, in 78 LC patients and 25 age- and gender-matched healthy controls.
Number of EPCs (E1, E2, E3) was lower (all p < 0.0001), whereas SDF-1α level and MCA were higher (p < 0.001) in study patients compared with healthy controls. Number of EPCs (E2, E3) was higher but MCA was lower (all p < 0.05) in Child's class A compared with Child's class B and C patients, although no difference in VEGF and SDF-1α levels were noted among these patients. Chronic hepatitis B and esophageal varices bleeding were independently, whereas chronic hepatitis C, elevated aspartate aminotransferase (AST), and decompensated LC were inversely and independently correlated with circulating EPC level (all p < 0.03). Additionally, angiogenesis and transwell migratory ability of EPCs were reduced in LC patients than in controls (all p < 0.001).
The results of this study demonstrated that level, angiogenic capacity, and function of circulating EPCs were significantly reduced, whereas plasma levels of SDF-1α and circulating MCA were substantially enhanced in cirrhotic patients.
PMCID: PMC3414826  PMID: 22809449
Liver cirrhosis; Circulating endothelial progenitor cells; Angiogenesis factors; Cellular apoptosis
20.  Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice 
Obesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice.
Methods and results
Eight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all p<0.001). Inflammation measured by mRNA expressions of IL-6, MMP-9, PAI-1 and leptin and protein expression of NF-κB was higher, whereas anti-inflammation measured by mRNA expressions of adiponectin and INF-γ was lower in obesity than in control and OR (all p<0.003). Oxidative protein expressions of NOX-1, NOX-2 and oxidized protein were higher, whereas expression of anti-oxidant markers HO-1 and NQO-1 were lower (all p<0.01); and apoptosis measured by Bax and caspase 3 was higher, whereas anti-apoptotic Bcl-2 was lower in obesity as compared with control and OR (all p<0.001). The expressions of fibrotic markers phosphorylated Smad3 and TGF-β were higher, whereas expression of anti-fibrotic phosphorylated Smad1/5 and BMP-2 were lower (all p<0.02); and LVEF was lower, whereas the LV remodeling was higher in obesity than in control and OR (all p<0.001).
Impaired LVEF, enhanced LV remodeling, inflammation, fibrosis, oxidative stress and apoptosis were reversed by reduction in mouse obesity.
PMCID: PMC3551744  PMID: 22784636
Obesity; Inflammation; Oxidative stress; Apoptosis; Fibrosis
21.  Obesity suppresses circulating level and function of endothelial progenitor cells and heart function 
Background and aim
This study tested the hypothesis that obesity suppresses circulating number as well as the function of endothelial progenitor cells (EPCs) and left ventricular ejection fraction (LVEF).
High fat diet (45 Kcal% fat) was given to 8-week-old C57BL/6 J mice (n = 8) for 20 weeks to induce obesity (group 1). Another age-matched group (n = 8) were fed with control diet for 20 weeks as controls (group 2). The animals were sacrificed at the end of 20 weeks after obesity induction.
By the end of study period, the heart weight, body weight, abdominal fat weight, serum levels of total cholesterol and fasting blood sugar were remarkably higher in group 1 than in group 2 (all p<0.01). The circulating level of EPCs (C-kit/CD31, Sca-1/KDR, CXCR4/CD34) was significantly lower in group 1 than in group 2 (p<0.03) at 18 h after critical limb ischemia induction. The angiogenesis and migratory ability of bone marrow-derived EPCs was remarkably impaired in group 1 compared to that in group 2 (all p<0.01). The repair ability of aortic endothelium damage by lipopolysaccharide was notably attenuated in group 1 compared with that in group 2 (p<0.01). Collagen deposition (Sirius red staining) and fibrotic area (Masson's Trichrome staining) in LV myocardium were notably increased in group 1 compared with group 2 (p<0.001). LVEF was notably lower, whereas LV end-diastolic and end-systolic dimensions were remarkably higher in group 1 than in group 2 (all p<0.001).
Obesity diminished circulating EPC level, impaired the recovery of damaged endothelium, suppressed EPC angiogenesis ability and LVEF, and increased LV remodeling.
PMCID: PMC3543390  PMID: 22747715
Obesity; Aortic endothelium; Endothelial progenitor cells; Angiogenesis; Left ventricular remodeling
22.  Plasma nuclear and mitochondrial DNA levels as predictors of outcome in severe sepsis patients in the emergency room 
Background and aim
The sensitivity and specificity of biomarkers and scoring systems used for predicting fatality of severe sepsis patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating plasma DNA levels in severe septic patients presenting at the Emergency Department (ED).
Sixty-seven consecutive patients with severe sepsis and 33 controls were evaluated. Plasma DNA levels were estimated by real-time quantitative polymerase chain reaction assay using primers for the human β-hemoglobin and ND2 gene. The patients’ clinical and laboratory data on admission were analyzed.
The median plasma nuclear and mitochondria DNA levels for severe septic patients on admission were significantly higher than those of the controls. The mean plasma nuclear DNA level on admission correlated with lactate concentration (γ = 0.36, p = 0.003) and plasma mitochondrial DNA on admission (γ = 0.708, p < 0.001). Significant prognostic factors for fatality included mechanical ventilation within the first 24 hours (p = 0.013), mean sequential organ failure assessment (SOFA) score on admission (p = 0.04), serum lactate (p < 0.001), and both plasma nuclear and mitochondrial DNA on admission (p < 0.001). Plasma mitochondrial DNA was an independent predictor of fatality by stepwise logistic regression such that an increase by one ng/mL in level would increase fatality rate by 0.7%.
Plasma DNA has potential use for predicting outcome in septic patients arriving at the emergency room. Plasma mitochondrial DNA level on admission is a more powerful predictor than lactate concentration or SOFA scores on admission.
PMCID: PMC3441240  PMID: 22720733
Hospital mortality; Mitochondrial DNA; Nucleus DNA; Severe sepsis
23.  Intra-coronary administration of tacrolimus markedly attenuates infarct size and preserves heart function in porcine myocardial infarction 
We test the hypothesis that intra-coronary tacrolimus administration can limit infarct size and preserve left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) through ligating left anterior descending coronary artery (LAD) in mini-pigs.
Twelve male mini-pigs were randomized into AMI-saline (MI-only) group and AMI-tacrolimus (MI-Tac) group that received intra-coronary saline (3.0 mL) and tacrolimus (0.5 mg in 2.5 mL saline) injection, respectively, beyond site of ligation 30 minutes after LAD occlusion.
Larger infarct area was noted in MI-only group (p < 0.001). Inflammatory biomarkers at protein [oxidative stress, tumor necrotic factor-α, nuclear factor-κB], gene (matrix metalloproteinase-9, plasminogen activator inhibitor-1), and cellular (CD40+, CD68+ inflammatory cells) levels were remarkably higher in MI-only animals (p < 0.01). Conversely, anti-inflammatory biomarkers at gene level (Interleukin-10), gene and protein level (endothelial nitric oxide synthase), and anti-oxidant biomarkers at both gene and protein levels [heme oxygenase 1, NAD(P)H:quinone oxidoreductase] were lower in MI-only group (p < 0.01). Number of apoptotic nuclei and apoptotic biomarkers expressions at gene and protein levels (Bax, caspase 3) were notably higher, whereas anti-apoptotic biomarkers at gene and protein levels (Bcl-2), LVEF, and fractional shortening were markedly lower in MI-only group (p < 0.001).
Intra-coronary administration of tacrolimus significantly attenuated infarct size and preserved LV function.
PMCID: PMC3408362  PMID: 22658082
24.  Statin pre-treatment is associated with lower platelet activity and favorable outcome in patients with acute non-cardio-embolic ischemic stroke 
Critical Care  2011;15(4):R163.
Statins reportedly have anti-inflammatory and anti-thrombotic effects aside from cholesterol-lowering. This study aimed to evaluate the effect of pre-existing statin use on platelet activation markers and clinical outcome in acute ischemic stroke patients.
This prospective study evaluated 172 patients with acute ischemic stroke divided in two groups: patients with pre-existing statin (n = 43) and without pre-existing statin (66 cases with statins initiated post-stroke and 63 without statin treatment). Platelet activation markers (CD62P and CD63) were measured by flow cytometry at different time points after stroke and analyzed with clinical outcome.
The CD62P and CD63 expressions on platelets were significantly lower in the patients with pre-existing statin use compared to the patients without pre-existing statin use on Day 1 post-stroke (p < 0.05). The CD62P expression was significantly lower in the patients with pre-existing statin use on 90 days after the acute stroke (p < 0.05). Patients with pre-existing statin use had lower incidences of early neurologic deterioration (END) than those without treatment (p < 0.05). Among several baseline clinical variables, admission NIHSS score, history of coronary artery disease, and pre-existing statin use were independent predictions of good clinical outcome at three months.
Pre-existing statin use is associated with decreased platelet activity as well as improved clinical outcome and reduced END in patients with acute ischemic stroke.
PMCID: PMC3387600  PMID: 21740551
flow cytometry; ischemic stroke; outcome; platelet activation
25.  Short telomeres in patients with chronic schizophrenia who show a poor response to treatment 
Telomere shortening has been observed in many human diseases, including atherosclerosis, cancer, aging syndromes, Alzheimer disease and vascular dementia. The present study aimed to investigate the mean telomere lengths of patients with schizophrenia.
We analyzed the lengths of telomeric DNA, comparing 2 groups of patients with schizophrenia (34 good responders and 34 poor responders). A control group of 76 healthy volunteers was also included. Blood samples were obtained, and telomere length was measured by Southern blot analysis on the mean length of terminal restriction fragment (TRF).
Compared with the control group, a significant amount of telomere shortening was found in peripheral blood leukocytes from patients with schizophrenia who experienced poor response to antipsychotics (p < 0.001).
Shortened telomere length in chronic schizophrenia may be a trait marker caused by oxidative stress, and the ensuing cellular dysfunction may be a factor contributing to the progressive deterioration in treatment-resistant schizophrenia.
PMCID: PMC2441885  PMID: 18592039
telomere; DNA restriction enzymes; blotting, Southern; schizophrenia

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