Hyperbaric oxygen therapy suppresses hypoxia and reoxygenation injury to retinal pigment epithelial cells through activating peroxisome proliferator activator receptor-alpha signalling.

Retinal ischemia followed by reperfusion (IR) is a common cause of many ocular disorders, such as age-related macular degeneration (AMD), which leads to blindness in the elderly population, and proper therapies remain unavailable. Retinal pigment epithelial (RPE) cell death is a hallmark of AMD. Hyperbaric oxygen (HBO) therapy can improve IR tissue survival by inducing ischemic preconditioning responses. We conducted an in vitro study to examine the effects of HBO preconditioning on oxygen-glucose deprivation (OGD)-induced IR-injured RPE cells. RPE cells were treated with HBO (100% O2 at 3 atmospheres absolute for 90 min) once a day for three consecutive days before retinal IR onset. Compared with normal cells, the IR-injured RPE cells had lower cell viability, lower peroxisome proliferator activator receptor-alpha (PPAR-α) expression, more severe oxidation status, higher blood-retinal barrier disruption and more elevated apoptosis and autophagy rates. HBO preconditioning increased PPAR-α expression, improved cell viability, decreased oxidative stress, blood-retinal barrier disruption and cellular apoptosis and autophagy. A specific PPAR-α antagonist, GW6471, antagonized all the protective effects of HBO preconditioning in IR-injured RPE cells. Combining these observations, HBO therapy can reverse OGD-induced RPE cell injury by activating PPAR-α signalling.

The Clinical Application of Pulsed Radiofrequency Induces Inflammatory Pain via MAPKs Activation: A Novel Hint for Pulsed Radiofrequency Treatment.

Pulsed radiofrequency (PRF) works by delivering short bursts of radiofrequency to a target nerve, thereby affecting nerve signal transduction to reduce pain. Although preliminary clinical investigations have shown that PRF treatment can be used safely as an alternative interventional treatment in patients with refractory pain conditions, unexpected damage to a normal nerve/ganglion is still one of the possible complications of using the PRF strategy. Noxious pain may also be triggered if PRF treatment accidentally damages an intact nerve. However, few studies in the literature have described the intracellular modifications that occur in neuronal cells after PRF stimulation. Therefore, in this study, we evaluated the effects of PRF on unimpaired nerve function and investigated the potential mechanisms of PRF-induced pain. Wistar rats were stimulated with 30-60 V of PRF for 6 min, and mechanical allodynia, cold hypersensitivity, cytokine and matrix metalloproteinase (MMP) production, and mitogen-activated protein kinase activity (p38 MAPK, ERK1/2, JNK/SAPK) were analyzed. The results indicated that PRF stimulation induced a significant algesic effect and nociceptive response. In addition, the protein array and Western blotting analyses showed that the clinical application of 60 V of PRF can induce the activation of MAPKs and the production of inflammatory cytokines and MMPs in the lumbar dorsal horn, which is necessary for nerve inflammation, and it can be suppressed by MAPK antagonist treatment. These results indicate that PRF stimulation may induce inflammation of the intact nerve, which in turn causes inflammatory pain. This conclusion can also serve as a reminder for PRF treatment of refractory pain.

Manipulating exchange bias by spin-orbit torque.

Exchange bias, a shift in the hysteresis loop of a ferromagnet arising from interfacial exchange coupling between adjacent ferromagnetic and antiferromagnetic layers, is an integral part of spintronic devices. Here, we show that spin-orbit torque generated from spin current, a promising approach to switch the ferromagnetic magnetization of next-generation magnetic random access memory, can also be used to manipulate the exchange bias. Applying current pulses to a Pt/Co/IrMn trilayer causes concurrent switching of ferromagnetic magnetization and exchange bias, but with different underlying mechanisms. This implies that the ferromagnetic magnetization and exchange bias can be manipulated independently. Our work demonstrates that spin-orbit torque in ferromagnet/antiferromagnet heterostructures facilitates independent manipulations of distinct magnetic properties, motivating innovative designs for future spintronics devices.

Hydrogen Protons Modulate Perivascular Axo-axonal Interactions in the Middle Cerebral Artery of Rats.

Previous studies have demonstrated that nicotine can induce relaxation of the middle cerebral artery (MCA). However, whether this relaxation is associated with the activity of sensory calcitonin gene-related peptide (CGRP) nerves and whether this is modulated by hydrogen protons (H), facilitating the release of CGRP from sensory CGRPergic nerve terminals in the MCA, remains unclear. In this study, we examined the role of H in the modulation of neurogenic vasomotor responses in the rat-isolated endothelium-denuded MCA. Wire myography was used to measure vasoreactivity and indicated that nicotine-induced relaxation was sensitive to tetrodotoxin and lidocaine and drastically reduced levels of guanethidine (an adrenergic neuronal blocker), N-nitro-L-arginine (L-NNA), CGRP8-37, vasoactive intestinal polypeptide (VIP)6-28, capsaicin, capsazepine (a transient receptor potential vanilloid-1 inhibitor), and tetraethylammonium. However, this nicotine-induced relaxation was not sensitive to propranolol. Lowering the pH of the buffer solution with HCl caused pH-dependent vasorelaxation and deceased intracellular pH in the MCA rings, which was sensitive to L-NNA, CGRP8-37, VIP6-28, capsazepine, 4-aminopyridine (a voltage-gated potassium channel antagonist), and paxilline (a large conductance Ca-activated K channel antagonist). However, HCl-induced relaxation was not inhibited by glibenclamide (an ATP-sensitive K channel blocker). These results suggested that electrical and chemical activation of cerebral perivascular adrenergic nerves led to the release of H, which then facilitated the release of NO, VIP, and CGRP, resulting in vasorelaxation. Lowering the pH of the buffer solution caused potassium channels of vascular smooth muscle cells and perivascular nerves to open. In conclusion, our results demonstrated that H may act as a modulator on MCA perivascular nerves and/or smooth muscles.

Anti-inflammatory effects of powdered product of Bu Yang Huan Wu decoction: Possible role in protecting against Transient Focal Cerebral Ischemia.

Bu Yang Huan Wu decoction (BYHW) is a traditional Chinese medicine (TCM) that consists of several herbs and has been used in patients with ischemic stroke for centuries. Although powdered formula of BYHW has widely been prescribed in clinic nowadays, evidence-based effectiveness and mechanism of action of BYHW powdered product in stroke remain to be characterized. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion for 24 h (ischemia/reperfusion; I/R) or sham surgery. After I/R, the rats were then given low dose (0.5 g/kg) and high dose (2.5 g/kg) of BYHW or vehicle by oral gavage twice a day for seven consecutive days. The results showed that I/R induced obvious cerebral infarction and neurobehavioral defects, in parallel with histological aberrations and extensive signaling of proinflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), in the stroke model. Post-I/R treatment with BYHW powdered product significantly reduced the infarct area and ameliorated neurofunctional defects in a dose-dependent manner. The dose dependence was associated with TNF-α downregulation and interleukin-10 (IL-10) induction. In summary, the present findings demonstrated that BYHW powdered product exhibited therapeutic efficacy for experimental stroke and a higher dose treatment may strengthen the effectiveness via inflammatory modulation.

Distant Intramuscular Metastases of Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: Metastasis of head and neck squamous cell carcinoma (HNSCC) usually occurs regionally in the neck lymph nodes, but also more infrequently at distant organs (eg, the lungs, bone, and liver). Intramuscular metastasis (IMM) has rarely been described. Therefore, we aimed to identify this disease characteristic and to evaluate available medical management options. METHODS: Data of surgically treated HNSCC patients (n = 1150) at the Chi Mei Medical Center, Taiwan (2005-2015), were retrospectively reviewed. Literature searches were also conducted (1985-2015) to analyze the behavior of HNSCC with distant IMMs. RESULTS: We identified 1 HNSCC patient with histopathologically proven IMMs. Ten similar cases were also identified in the available literature. Two-thirds of lesions arose in patients with laryngeal/hypopharyngeal malignancies, and two-thirds of lesions were located in the lower limbs. Lesions were subjectively painful and usually had rim enhancement with central hypoattenuation in contrast-enhanced computed tomography/magnetic resonance imaging. The mean duration between primary tumor diagnosis and secondary lesion detection was 13.7 months. No patient survived more than 2 years after establishing a diagnosis of HNSCC with IMMs. CONCLUSIONS: Distant IMMs are extremely rare in HNSCC patients and have a poor clinical outcome. Differentiating this disease from sarcoma via anatomic distribution or diagnostic imaging studies is not straightforward. Biopsies for histopathologic examination are mandatory. Treatment of HNSCC patients with IMMs is mainly palliative for life quality preservation and not lifetime prolongation. Radiotherapy is established as a first-line treatment for symptom control with surgical intervention usually preserved for refractory cases.

Baicalein inhibits matrix metalloproteinase 1 expression via activation of TRPV1-Ca-ERK pathway in ultraviolet B-irradiated human dermal fibroblasts.

Increased matrix metalloproteinase 1 (MMP-1) expression is a feature of photo-aged skin. We investigated the effects of baicalein and sulphoraphane on ultraviolet B (UVB) irradiation-induced MMP-1 expression and apoptosis using human dermal fibroblasts. UVB irradiation not only increased MMP-1 expression, but also caused apoptosis. Both baicalein and sulphoraphane protected cells from UVB irradiation-induced apoptosis, but only baicalein inhibited MMP-1 expression. UVB irradiation activated 12-lipoxygenase, and its product, 12-hydroxyeicosatetraenoic acid, activated TRPV1 channels. The resulting UVB irradiation-induced Ca2+ increase was blocked by the 12-lipoxygenase inhibitor baicalein and the TRPV1 blocker capsazepine, but not by the Nrf2 inducer sulphoraphane. UVB irradiation also increased ROS generation and decreased Nrf2 protein levels. UVB irradiation-induced MMP-1 expression was blocked by the Ca2+ chelator BAPTA, by capsazepine and by TRPV1 silencing. However, induction was unaffected by the antioxidant N-acetylcysteine. ERK phosphorylation and JNK phosphorylation were induced by UVB irradiation, but only ERK phosphorylation was Ca2+ sensitive. Increased MMP-1 expression was blocked by PD98059, but not by SP600125. Thus, increased MMP-1 expression is mediated by increased cytosolic Ca2+ and ERK phosphorylation. UVB irradiation-induced ROS generation is also Ca2+ sensitive, and UVB irradiation-induced apoptosis is caused by increased ROS. Thus, baicalein, by blocking the UVB irradiation-induced cytosolic Ca2+ increase, protects cells from UVB irradiation-induced MMP-1 expression and apoptosis. In contrast, sulphoraphane, by decreasing cellular ROS, protects cells from only UVB-induced apoptosis. Thus, targeting 12-lipoxygenase may provide a therapeutic approach to improving the health of photo-aged human skin.

Neuroprotective Effects of Collagen-Glycosaminoglycan Matrix Implantation following Surgical Brain Injury.

BACKGROUND: Neurological deficits following neurosurgical procedures are inevitable; however, there are still no effective clinical treatments. Earlier reports revealed that collagen-glycosaminoglycan (CG) matrix implantation promotes angiogenesis, neurogenesis, and functional recovery following surgical brain injury (SBI). The present study was conducted to further examine the potential neuroprotective effects of collagen-glycosaminoglycan (CG) matrix implantation following neurosurgery. METHODS: CG implantation was performed in the lesion cavity created by surgical trauma. The Sprague-Dawley rat model of SBI was used as established in the previous study by the author. The rats were divided into three groups as follows: (1) sham (SHAM), (2) surgery-induced lesion cavity (L), and (3) CG matrix implantation following surgery-induced lesion cavity (L+CG). Proinflammatory (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)) and anti-inflammatory (IL-10 and granulocyte-macrophage colony-stimulating factor (GMCSF)) cytokine expression was evaluated by enzyme-linked immunosorbent assays. Microglial activation was evaluated by immunohistochemistry, and the neuroprotective effect of CG matrix implantation was evaluated by an immunohistochemical study of microglia ED-1 and IBA-1 (activated microglia) and myeloperoxidase (MPO) and by the analysis of IL-6, IL-10, TNF-α, NF-κB, and GMCSF cytokine levels. Apoptosis was also assessed using a TUNEL assay. RESULTS: The results showed that CG matrix implantation following surgically induced lesions significantly decreased the density of ED-1, IBA-1, and MPO (activated microglia). The tissue concentration of proinflammatory cytokines, such as TNF-α, IL-6, and NF-κB was significantly decreased. Conversely, the anti-inflammatory cytokines GMCSF and IL-10 were significantly increased. CONCLUSIONS: Implantation of the CG matrix following SBI has neuroprotective effects, including the suppression of microglial activation and the production of inflammatory-related cytokines.

A new copper ionophore DPMQ protects cells against ultraviolet B irradiation by inhibiting the TRPV1 channel.

Copper is more likely than iron to generate reactive oxygen species (ROS) in a redox reaction due to its higher electrochemical reactivity. This study examined the effect of a newly synthesized Cu2+ binding compound, (E)-2-(4-(dimethylamino)phenylimino)methyl)quinolin-8-ol (DPMQ), on ultraviolet B (UVB) irradiation-induced cytotoxicity in human dermal fibroblasts. DPMQ induced Cu2+ influx as effectively as disulfiram, a Cu2+ ionophore anticancer drug. However, disulfiram induced ROS generation, mitochondrial dysfunction, and apoptosis in fibroblasts in a Cu2+ -dependent manner, whereas DPMQ was not only nontoxic, but protected cells against UVB irradiation-induced apoptosis in a Cu2+ -independent manner. UVB irradiation induced a Ca2+ -dependent increase in ROS generation, a decrease in Nrf2 levels, and activation of the mitochondrial apoptotic pathway, and these effects were prevented by DPMQ, which also increased Nrf2 nuclear translocation in a Cu2+ -independent manner. UVB irradiation activated 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid (12-HETE), a product of 12-lipoxygenase, activated the TRPV1 channel. DMPQ did not act as a Ca2+ chelator, but inhibited the cytosolic Ca2+ increase induced by 12-HETE or capsaicin, but not that induced by bradykinin or ATP. Blockade of Ca2+ influx by pharmacological inhibition or silencing of the TRPV1 channel or chelation of cytosolic Ca2+ inhibited the UVB irradiation-induced Nrf2 reduction, ROS generation, mitochondrial dysfunction, and apoptosis. Taken together, our results suggest that Ca2+ influx via the TRPV1 channel is responsible for UVB irradiation-induced cytotoxicity and that DPMQ protects cells against UVB irradiation by inhibiting the TRPV1 channel and stabilizing Nrf2, and could thus be a potentially useful compound for the treatment of free radical-induced diseases.

Ultraviolet B irradiation increases keratin 1 and keratin 10 expressions in HaCaT keratinocytes via TRPV1 activation and ERK phosphorylation.

In this study, we characterized the effect of ultraviolet B (UVB) irradiation with or without epidermal growth factor (EGF) on the regulation of keratinocyte differentiation under physiological concentration of Ca2+ (1.8 mM). In addition, growth factor deprivation used to measure signal transduction and kinase phosphorylation in many studies is physiologically unreal. Therefore, 1% of serum was also included in all experiment. We found that UVB irradiation Ca2+ dependently induced morphological differentiation and increased keratin 1 and 10 (K1/K10) expressions. Both were inhibited by treatment of cells with EGF. In quiescent cells, phosphorylation of ERK was stimulated by acute EGF treatment, while it rapidly desensitized in chronic EGF treatment or 1% serum exposure. UVB irradiation-induced keratinocyte differentiation required Ca2+ influx through TRPV1. Ca2+ -dependent phosphorylation of ERK was responsible for the expression of K1/10. Cotreatment of cells with EGF during UVB irradiation inhibits the UVB irradiation-induced differentiation by desensitizing ERK phosphorylation.

Quality of life of breast and cervical cancer survivors.

BACKGROUND: Breast and cervical cancer are the most common cancers affecting women. The symptom distresses experienced by cancer survivors are critical factors influencing their quality of life (QOL). This study investigated the QOL of breast and cervical cancer survivors, their physical, psychological and social conditions. METHODS: The participants were older than 20 years, had been diagnosed with breast or cervical cancer for more than 2 years, and had completed their cancer treatment. The survey incorporated the QOL questionnaires developed by the European Organization of Research and Treatment for Cancer and a self-designed questionnaire. RESULTS: The mean age at diagnosis was 48.89 ± 8.53 years for the breast cancer survivors and 49.00 ± 10.30 years for the cervical cancer survivors. The corresponding QOL scores were 75.33 ± 20.25 and 75.56 ± 17.93. The factors influencing QOL of breast cancer survivors were household income, number of comorbidities, stage of cancer, type of cancer treatment and duration of illness, whereas the factor related to QOL of cervical cancer survivors was only household income. CONCLUSIONS: The QOL of the two groups was similar. Healthcare providers should demonstrate greater concern toward breast and cervical cancer survivors.

Baicalein increases keratin 1 and 10 expression in HaCaT keratinocytes via TRPV4 receptor activation.

In this study, we characterized the effect of baicalein on the regulation of keratinocyte differentiation and proliferation, which are abnormal in atopic dermatitis or psoriasis. Treatment of HaCaT keratinocytes with 10 µm baicalein slightly inhibited cell growth, caused morphological differentiation and increased expression of keratins 1 and 10 (K1/K10) without affecting ROS generation, cytochrome c release or apoptosis. Baicalein treatment caused growth arrest in G0 /G1 phase and also induced Ca(2+) influx via TRPV4 receptor activation. Phosphorylation of ERK, Akt and p38 MAPK, but not JNK, was increased by baicalein, and inhibition of phosphorylation of ERK, but not that of Akt or p38 MAPK, blocked the baicalein-induced increase in K1/K10 expression, suggesting that ERK activation is involved in this increase. Removal of extracellular Ca(2+) or blockade of Ca(2+) influx by pharmacological inhibition or silencing of the TRPV4 receptor did not affect growth arrest, ROS generation or apoptosis, but inhibited baicalein-induced ERK phosphorylation and K1/K10 expression. Thus, baicalein treatment increases differentiation, and decreases proliferation, of keratinocytes. The mechanism of differentiation of keratinocytes is distinct from that of proliferation, the former being Ca(2+) dependent and the latter Ca(2+) independent.

Experience in Reconstruction for Small Digital Defects With Free Flaps.

Traumatic injuries to the digits resulting in soft tissue or bone loss require reconstruction. Traditionally, local flaps, such as homodigital flaps, heterodigital flaps, pedicled flaps, or distant flaps, are used for digital resurfacing. However, free tissue transfers can be used in selected patients. In this study, we present the use of different free flaps including groin skin flaps, groin osteocutaneous flaps, groin chimeric flaps, second dorsal metacarpal artery flaps, and partial toe flaps for digital reconstruction. A total of 19 digits were treated with 16 free flaps in our hospital. Of the flaps used, 5 were free groin skin flaps, 4 were free partial toe flaps, 3 were free groin chimeric flaps, 2 were free groin osteocutaneous flaps, and 2 were free second dorsal metacarpal artery flaps. The average flap size was 4.7 × 2.0 cm (range, 1.5 × 1 to 5 × 4 cm), and the average operative time was 6.0 hours (range, 4-9 hours). All flaps survived without partial or total necrosis. In conclusion, the free flap is a reliable and safe alternative for digital reconstruction. Moreover, the free groin flap provides not only a chimeric pattern for multiple fingers coverage but also an osteocutaneous pattern for thumb lengthening. The free second dorsal metacarpal artery flap provides a tenocutaneous pattern for tendon reconstruction and soft tissue coverage simultaneously, and the free partial toe flap is an excellent alternative for pulp reconstruction in terms of aesthetic appearance and functional outcome.

The impact of physical fitness and body mass index in children on the development of acute mountain sickness: A prospective observational study.

BACKGROUND: Acute mountain sickness (AMS) is commonly found among people traveling above 2500 m. We investigated whether the occurrence of AMS is related to differences in individual physical fitness and BMI in subjects 11-13 years of age. METHODS: This study was conducted at Xue Mountain, Taiwan (elevation of 3886 m) between June 13, 2011 and June 17, 2011. Subjects were asked to ascend from Taipei City (25 m) to the summit (3886 m) over 3 days and 2 nights. Gender, age, weight, height, and fitness index (determined using a 3-minute step test) were recorded at sea level before ascent. The Lake Louise AMS score was used to record symptoms and diagnose AMS. RESULTS: A total of 179 subjects (mean age: 11.8 years; 102 males, 77 females) were included in the analysis. A total of 44.7% of subjects were diagnosed with AMS. Male gender (p = 0.004) and elevated body mass index (BMI) (p < 0.001) were each associated with the development of AMS. However the physical fitness index was comparable in subjects with and without AMS (67.8 ± 10.1 vs. 68.0 ± 9.3, p = 0.9). CONCLUSIONS: This study shows that both BMI and male gender were associated with the development of AMS in 11-13 year old children. Physical fitness was not associated with the occurrence of AMS.

Epidemiological profile of Dupuytren's disease in Taiwan (Ethnic Chinese): a nationwide population-based study.

BACKGROUND: The epidemiologic profile of ethnic Chinese patients with Dupuytren's disease is unknown. We therefore investigated the epidemiology of Dupuytren's disease using Taiwan's National Health Insurance Research Database. METHODS: Patients who filed claims for treatment for Dupuytren's disease between January 2000 and December 2011 were identified in the database. Age- and gender-specific incidences were estimated by dividing the incidence number by population data. RESULTS: We identified 1,078 patients with Dupuytren's disease (681 men, 397 women; male/female ratio: 1:1.72). The annual incidence rate ranged from 0.39-0.63/10(5) for men and 0.14-0.44/10(5) for women. A trend analysis revealed a rising trend in the annual incidence from 2001 to 2011 (p = 0.0199). The prevalence rate increased steadily from 0.46/10(5) in 2000 to 4.52/10(5) in 2011 (p = 0.0186). The mean age at onset was significantly higher in men than in women (60.7 ± 18.4 vs. 53.7 ± 15.5 years). Peak age at onset for men was 70-79 (28.1%) and for women was 50-59 (33.5%). Men > 60 years old had higher incidence rates than did women (incidence rate ratios: 2.0, 4.5, and 6.6 for those 60-69, 70-79, and ≥ 80, respectively). Hypertension (29.6%), diabetes mellitus (21.9%), hyperlipidemia (14.8%), ischemic heart disease (10.5%), and chronic obstructive pulmonary disease (8.0%) were the most common comorbidities. CONCLUSIONS: The incidence and prevalence of Dupuytren's disease and the male/female ratio were significantly lower in ethnic Chinese than in Western ethnic groups. Moreover, the age at onset was significantly lower in ethnic Chinese women. However, the incidences of three comorbidities (hypertension, diabetes mellitus, and hyperlipidemia) were similar to those in other ethnicities.

Rate of ascent and acute mountain sickness at high altitude.

OBJECTIVE: To examine the effect of ascent rate on the induction of acute mountain sickness (AMS) in young adults during a climb to Jiaming Lake (3350 m) in Taiwan. DESIGN: Prospective, nonrandomized. SETTING: Climb from 2370 to 3350 m. PARTICIPANTS: Young adults (aged 18 to 26 years) (N = 91) chose to participate in either the fast ascent (3 days; n = 43) or slow ascent (4 days; n = 48) group (1 and 2). ASSESSMENT OF RISK FACTORS: Two criteria were used to define AMS. A Lake Louise score ≥3 and Lake Louise criteria [in the setting of a recent gain in altitude, the presence of headache and at least 1 of gastrointestinal discomfort (anorexia, nausea, or vomiting), fatigue or weakness, dizziness or lightheadedness, or difficulty sleeping]. MAIN OUTCOME MEASURES: Heart rate, blood oxygen saturation (SaO2), and symptoms of AMS were monitored each morning and evening. RESULTS: Baseline characteristics were similar between groups, except for significant differences in history of alcohol consumption (P = 0.009) and climbing experience above 3000 m (P < 0.001). The incidence of AMS was not associated with the rate of ascent. Acute mountain sickness was most prevalent in group 1 on day 2 in the evening and in group 2 on day 3 in the evening. In both groups, AMS correlated with the initial reduction in SaO2. Body mass index (BMI) >24 kg/m was identified as a significant risk factor for AMS. CONCLUSIONS: The development of AMS was closely associated with an initial reduction in SaO2. A BMI >24 kg/m also contributed to the occurrence of AMS. CLINICAL RELEVANCE: These findings indicate that factors other than ascent rate should be considered when trying to ameliorate the risk of AMS.

Zoledronic acid infusion for lumbar interbody fusion in osteoporosis.

BACKGROUND: Clinical outcomes of intravenous (IV) infusion of zoledronic acid (ZOL) for lumbar interbody fusion surgery (LIFS) remain unknown. We investigated the efficacy of IV ZOL on clinical outcome and bone fusion after LIFS. MATERIALS AND METHODS: We retrospectively analyzed 64 patients with both degenerative lumbar spondylolisthesis and osteoporosis who underwent LIFS from January 2007 to April 2010. All patients were followed up for 2 y. Thirty-two were treated with an IV infusion of ZOL 3 d after surgery and a second injection 1 y later, and the other 32 patients did not receive ZOL. Preoperatively and every 3 mo postoperatively, oswestry disability index questionnaire and visual analog scale (VAS) scores for back and leg were compared. Preoperative and final postoperative follow-up to evaluate for subsequent compression fractures were also performed. Pedicle screw loosening, cage subsidence, and fusion rate were documented 2 y after surgery. RESULTS: At 2-y follow-up, a solid fusion was achieved in 75% of the ZOL group and only 56% of the control group. At final follow up, the incidence of final subsequent vertebral compression fractures (19% of the ZOL group and 51% of the control group, P = 0.006), pedicle screw loosening (18% of the ZOL group and 45% of the control group, P = 0.03), and cage subsidence >2 mm (28% of the ZOL group and only 54% of the control group, P = 0.04) were significantly lower in the ZOL group than in the control group. The ZOL group demonstrated improvement in VAS (for leg pain VAS, 2/10 for the ZOL group and 5/10 for the control group; for back pain VAS, 2/10 for the ZOL group and 6/10 for the control group) and oswestry disability index scores (7/25 for the ZOL group and 16/25 for the control group). CONCLUSIONS: ZOL treatment has beneficial effects on instrumented LIFS both radiographic and clinically. Thus, ZOL treatment can be recommended for osteoporosis patients undergoing LIFS.

Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in a Randomized Phase III Trial: A Post Hoc Analysis.

Objective: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. Approach: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized Phase III trial that included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). Results: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (p = 0.0001). In subgroup analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (p < 0.0001); plantar ulcers (p = 0.0016), ulcer size ≥5 cm2 (p = 0.0122), ulcer duration ≥3 months (p = 0.0043); for patients with HbA1c ≥9% (p = 0.0285); and patients with BMI ≥25 (p = 0.0005). Innovation: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. Conclusions: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

Design, synthesis and antiproliferative evaluation of fluorenone analogs with DNA topoisomerase I inhibitory properties.

A series of 2,7-diamidofluorenones were designed, synthesized, and screened by SRB assay. Some synthesized compounds exhibited antitumor activities in submicromolar range. Ten compounds (3a, 3b, 3c, 3g, 3j, 3l, 4a, 4h, 4i, and 4j) were also selected by NCI screening system and 3c (GI50=1.66 µM) appeared to be the most active agent of this series. Furthermore, 3c attenuated topoisomerase I-mediated DNA relaxation at low micromolar concentrations. These results indicated that fluorenones have potential to be further developed into anticancer drugs.

Synthesis, telomerase evaluation and anti-proliferative studies on various series of diaminoanthraquinone-linked aminoacyl residue derivatives.

Four series of compounds containing an anthraquinone-linked moiety and symmetrical or asymmetrical aminoacyl residues in side chains at positions 1,4-, 1,5-, 2,6-, and 2,7- were synthesized and evaluated for their inhibitory effects toward telomerase and hTERT expression. Of these, only compound B11 showed selective inhibition of telomerase activity. Although it is not as competent as several of the anthraquinones we identified previously, nevertheless, the result is consistent with that the general structure moiety at the 1,5-position of diaminoanthraquinone-linked compound is important for the telomerase inhibitory activity. Interestingly, compounds A6, A8, C8, and D8 exhibited selective repressing activities toward hTERT expression and showed less effect toward proliferation of the treated cancer cells. Although it is not apparent which structure moiety is responsible for the telomerase repression effects of these compounds, they could be further developed as potential anti-tumor agents.