Developmental organization of neural dynamics supporting auditory perception.

PURPOSE: A prominent view of language acquisition involves learning to ignore irrelevant auditory signals through functional reorganization, enabling more efficient processing of relevant information. Yet, few studies have characterized the neural spatiotemporal dynamics supporting rapid detection and subsequent disregard of irrelevant auditory information, in the developing brain. To address this unknown, the present study modeled the developmental acquisition of cost-efficient neural dynamics for auditory processing, using intracranial electrocorticographic responses measured in individuals receiving standard-of-care treatment for drug-resistant, focal epilepsy. We also provided evidence demonstrating the maturation of an anterior-to-posterior functional division within the superior-temporal gyrus (STG), which is known to exist in the adult STG. METHODS: We studied 32 patients undergoing extraoperative electrocorticography (age range: eight months to 28 years) and analyzed 2,039 intracranial electrode sites outside the seizure onset zone, interictal spike-generating areas, and MRI lesions. Patients were given forward (normal) speech sounds, backward-played speech sounds, and signal-correlated noises during a task-free condition. We then quantified sound processing-related neural costs at given time windows using high-gamma amplitude at 70-110 Hz and animated the group-level high-gamma dynamics on a spatially normalized three-dimensional brain surface. Finally, we determined if age independently contributed to high-gamma dynamics across brain regions and time windows. RESULTS: Group-level analysis of noise-related neural costs in the STG revealed developmental enhancement of early high-gamma augmentation and diminution of delayed augmentation. Analysis of speech-related high-gamma activity demonstrated an anterior-to-posterior functional parcellation in the STG. The left anterior STG showed sustained augmentation throughout stimulus presentation, whereas the left posterior STG showed transient augmentation after stimulus onset. We found a double dissociation between the locations and developmental changes in speech sound-related high-gamma dynamics. Early left anterior STG high-gamma augmentation (i.e., within 200 ms post-stimulus onset) showed developmental enhancement, whereas delayed left posterior STG high-gamma augmentation declined with development. CONCLUSIONS: Our observations support the model that, with age, the human STG refines neural dynamics to rapidly detect and subsequently disregard uninformative acoustic noises. Our study also supports the notion that the anterior-to-posterior functional division within the left STG is gradually strengthened for efficient speech-sound perception after birth.

Multifunctional sonosensitizers in sonodynamic cancer therapy.

Phototherapy, including photodynamic therapy and photothermal therapy, has the potential to treat several types of cancer. However, to be an effective anticancer treatment, it has to overcome limitations, such as low penetration depth, low target specificity, and resistance conferred by the local tumor microenvironment. As a non-invasive technique, low-intensity ultrasound has been widely used in clinical diagnosis as it exhibits deeper penetration into the body compared to light. Recently, sonodynamic therapy (SDT), a combination of low-intensity ultrasound with a chemotherapeutic agent (sonosensitizer), has been explored as a promising alternative for cancer therapy. As all known cancer treatments such as chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, and drug delivery have been advanced independently enough to complement others substantially, the combination of these therapeutic modalities with SDT is opportune. This review article highlights the recent advances in SDT in terms of sonosensitizers and their formulations and anticancer therapeutic efficacy. Also discussed is the potential of SDT in combination with other modalities to address unmet needs in precision medicine.

Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model.

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents; however, their clinical effectiveness is highly variable, with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic doses. CD101, but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs are limited by penetration at the site of infection and have implications for clinical outcomes and emergence of resistance in patients with IAC.

Acupuncture for chronic fatigue syndrome and idiopathic chronic fatigue: a multicenter, nonblinded, randomized controlled trial.

BACKGROUND: The causes of chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF) are not clearly known, and there are no definitive treatments for them. Therefore, patients with CFS and ICF are interested in Oriental medicine or complementary and alternative medicine. For this reason, the effectiveness of complementary and alternative treatments should be verified. We investigated the effectiveness of two forms of acupuncture added to usual care for CFS and ICF compared to usual care alone. METHODS: A three-arm parallel, non-blinded, randomized controlled trial was performed in four hospitals. We divided 150 participants into treatment and control groups at the same ratio. The treatment groups (Group A, body acupuncture; Group B, Sa-am acupuncture) received 10 sessions for 4 weeks. The control group (Group C) continued usual care alone. The primary outcome was the Fatigue Severity Scale (FSS) at 5 weeks after randomization. Secondary outcomes were the FSS at 13 weeks and a short form of the Stress Response Inventory (SRI), the Beck Depression Inventory (BDI), the Numeric Rating Scale (NRS), and the EuroQol-5 Dimension (EQ-5D) at 5 and 13 weeks. RESULTS: Group A showed significantly lower FSS scores than Group C at 5 weeks (P = 0.023). SRI scores were significantly lower in the treatment groups than in the control group at 5 (Group A, P = 0.032; B, P <0.001) and 13 weeks (Group A, P = 0.037; B, P <0.001). Group B showed significantly lower BDI scores than Group C at 13 weeks (P = 0.007). NRS scores from the treatment groups were significantly reduced compared to control at 5 (Group A and B, P <0.001) and 13 weeks (Group A, P = 0.011; B, P = 0.002). CONCLUSIONS: Body acupuncture for 4 weeks in addition to usual care may help improve fatigue in CFS and ICF patients. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0000508; Registered on 12 August 2012.

Electroacupuncture for chemotherapy-induced peripheral neuropathy: study protocol for a pilot multicentre randomized, patient-assessor-blinded, controlled trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting side effect of neurotoxic chemotherapeutic agents. CIPN can lead not only to loss of physical function, difficulties in activities of daily living (ADLs), and decreased quality of life, but also to dose reduction, delay or even cessation of treatment. Currently, there are few proven effective treatments for CIPN. This randomized controlled clinical trial is designed to evaluate the effects and safety of electroacupuncture (EA) for patients with CIPN. METHODS/DESIGN: This is a multicenter, two-armed, parallel-design, patient-assessor-blinded, randomized, sham-controlled clinical trial. Forty eligible patients with CIPN will be randomized in a ratio of 1:1 to the EA or sham EA arms. During the treatment phase, patients will undergo eight sessions of verum EA or sham EA twice weekly for four weeks, and then will be followed-up for eight weeks. Electrical stimulation in the EA group will consist of a mixed frequency of 2/120 Hz and 80% of bearable intensity. Sham EA will be applied to non-acupoints, with shallow needle insertion and no current. All outcomes and analyses of results will be assessed by researchers blinded to treatment allocation. The effects of EA on CIPN will be evaluated according to both subjective and objective outcome measures. The primary outcome measure will be the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire to assess CIPN (QLQ-CIPN20). The secondary outcome measures will be the results on the numerical rating scale, the Semmes-Weinstein monofilament test, the nerve conduction study, and the EORTC QLQ-C30, as well as the patient's global impression of change and adverse events. Safety will be assessed at each visit. DISCUSSION: The results of this on-going study will provide clinical evidence for the effects and safety of EA for CIPN compared with sham EA. TRIAL REGISTRATION: Clinical Research Information Service: KCT0000506.

Acupuncture for lateral epicondylitis (tennis elbow): study protocol for a randomized, practitioner-assessor blinded, controlled pilot clinical trial.

BACKGROUND: Lateral epicondylitis is the most frequent cause of pain around the elbow joint. It causes pain in the region of the elbow joint and results in dysfunction of the elbow and deterioration of the quality of life. The purpose of this study is to compare the effects of ipsilateral acupuncture, contralateral acupuncture and sham acupuncture on lateral epicondylitis. METHODS/DESIGN: Forty-five subjects with lateral epicondylitis will be randomized into three groups: the ipsilateral acupuncture group, contralateral acupuncture group and the sham acupuncture group. The inclusion criteria will be as follows: (1) age between 19 and 65 years with pain due to one-sided lateral epicondylitis that persisted for at least four weeks, (2) with tenderness on pressure limited to regions around the elbow joint, (3) complaining of pain during resistive extension of the middle finger or the wrist, (4) with average pain of NRS 4 or higher during the last one week at a screening visit and (5) voluntarily agree to this study and sign a written consent. Acupuncture treatment will be given 10 times in total for 4 weeks to all groups. Follow up observations will be conducted after the completion of the treatment, 8 weeks and 12 weeks after the random assignment. Ipsilateral acupuncture group and contralateral acupuncture group will receive acupuncture on LI4, TE5, LI10, LI11, LU5, LI12 and two Ashi points. The sham acupuncture group will receive treatment on acupuncture points not related to the lateral epicondylitis using a non-invasive method. The needles will be maintained for 20 minutes. The primary outcome will be differences in the visual analogue scale (VAS) for elbow pain between the groups. The secondary outcome will be differences in patient-rated tennis elbow evaluation (PRTEE), pain-free/maximum grip strength (Dynamometer), pressure pain threshold, clinically relevant improvement, patient global assessment, and the EQ-5D. The data will be analyzed with the paired t-test and ANCOVA (P <0.05). DISCUSSION: The results of this study will allow evaluation of contralateral acupuncture from two aspects. First, if the contralateral acupuncture shows the effects similar to ipsilateral acupuncture, this will establish clinical basis for contralateral acupuncture. Second, if the effects of contralateral acupuncture are not comparable to the effects of ipsilateral acupuncture, but are shown to be similar to the effects of the sham acupuncture, we can establish the basis for using the same acupoints of the unaffected side as a control in acupuncture clinical studies. TRIAL REGISTRATION: This trial has been registered with the 'Clinical Research Information Service (CRIS)', Republic of Korea: KCT0000628.

An open-label study of effects of acupuncture on chronic fatigue syndrome and idiopathic chronic fatigue: study protocol for a randomized controlled trial.

BACKGROUND: Even though chronic fatigue syndrome and idiopathic chronic fatigue are quite common, there are no clearly known causes. Most treatments are therefore symptomatic in nature, and chronic fatigue syndrome and idiopathic chronic fatigue patients are highly interested in using oriental medicine or complementary and alternative medicine treatment. Acupuncture, one of the major treatments used in oriental medicine, is effective in treating various diseases. This study will attempt to analyze the effectiveness and safety of acupuncture in the treatment of chronic fatigue by comparing the two treatment groups (body acupuncture, Sa-am acupuncture) and the control group (usual care). METHODS/DESIGN: This study consists of a four-center, three-arm, randomized, controlled, and open-label trial. One hundred and fifty participants are randomly divided into treatment groups A and B and a control group. The treatment groups will receive acupuncture treatments either two or three times per week for a total of 10 sessions over a period of 4 weeks. The control group will not receive acupuncture treatments and will continue their usual care during this period. The primary outcome variable is the Fatigue Severity Scale, which will be utilized 5 weeks after randomization. Secondary outcome variables are the Fatigue Severity Scale at 13 weeks, a short form of the Stress Response Inventory, the Beck Depression Inventory, the Numeric Rating Scale, and the EuroQol-5 Dimension at 5 and 13 weeks after randomization. DISCUSSION: This study will provide evidence with high external validity on the effectiveness and safety of acupuncture as a treatment for chronic fatigue syndrome and idiopathic chronic fatigue. TRIAL REGISTRATION: Clinical Research Information Service KCT0000508.

Efficacy of moxibustion for pre- or stage I hypertension: study protocol for a pilot randomized controlled trial.

BACKGROUND: Hypertension is a risk factor for cardiovascular disease, and the prevalence of hypertension tends to increase with age. Current treatments for hypertension have adverse side effects and poor adherence. The purpose of this study is to evaluate the effects of moxibustion on blood pressure in individuals with pre- or stage I hypertension. METHODS/DESIGN: Forty-five subjects with pre- or stage I hypertension will be randomized into three groups: treatment group A (2 times/week), treatment group B (3 times/week), and the control group (non-treated group). The inclusion criteria will be as follows: (1) aged between 19 and 65 years; (2) prehypertension or stage I hypertension (JNC 7, Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure); (3) the participants are volunteers and written consent obtained.The participants in the treatment group A will undergo indirect moxibustion 2 times per week for 4 weeks, and the participants in the treatment group B will undergo indirect moxibustion 3 times per week for 4 weeks. The participants in the control group (non-treated group) will maintain their current lifestyle, including diet and exercise. The use of antihypertensive medication is not permitted. The primary endpoint will be a change in patient blood pressure. The secondary endpoints will be the body mass index, lipid profile, EuroQol and Heart Rate Variability. The data will be analyzed with the Student's t-test and analysis of variance (ANOVA) (p < 0.05). DISCUSSION: The results of this study will help to establish the optimal approach for the care of adults with pre- or stage I hypertension. TRIAL REGISTRATION: Clinical Research Information Service KCT0000469.

Cupping for treating neck pain in video display terminal (VDT) users: a randomized controlled pilot trial.

OBJECTIVES: This was a randomized controlled pilot trial to evaluate the effectiveness of cupping therapy for neck pain in video display terminal (VDT) workers. METHODS: Forty VDT workers with moderate to severe neck pain were recruited from May, 2011 to February, 2012. Participants were randomly allocated into one of the two interventions: 6 sessions of wet and dry cupping or heating pad application. The participants were offered an exercise program to perform during the participation period. A 0 to 100 numeric rating scale (NRS) for neck pain, measure yourself medical outcome profile 2 score (MYMOP2 score), cervical spine range of motion (C-spine ROM), neck disability index (NDI), the EuroQol health index (EQ-5D), short form stress response inventory (SRI-SF) and fatigue severity scale (FSS) were assessed at several points during a 7-week period. RESULTS: Compared with a heating pad, cupping was more effective in improving pain (adjusted NRS difference: -1.29 [95% CI -1.61, -0.97] at 3 weeks (p=0.025) and -1.16 [-1.48, -0.84] at 7 weeks (p=0.005)), neck function (adjusted NDI difference: -0.79 [-1.11, -0.47] at 3 (p=0.0039) and 7 weeks (p<0.0001)) and discomfort (adjusted MYMOP2 difference score: -0.72 [-1.04 to -0.40] at 3 weeks and -0.92 [-1.24, -0.60] at 7 weeks). Significant improvement in EQ-5D was observed at 7 weeks (1.0 [0.88, 1.0] with cupping and 0.91 [0.86, 0.91] with heating pad treatment, p=0.0054). Four participants reported mild adverse events of cupping. CONCLUSION: Two weeks of cupping therapy and an exercise program may be effective in reducing pain and improving neck function in VDT workers.

A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase.

RATIONALE: Cellular redox homeostasis altered by excessive production of reactive oxygen species (ROS) and weakening of the antioxidant defense leads to oxidative stress. Oxidative stress is characterized as a decrease in glutathione/glutathione disulfide (GSH/GSSG) and the triggering of a number of the redox-sensitive signaling cascades. Recent studies have demonstrated that ROS play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. OBJECTIVES: Here we characterized for the first time the protective properties of a new hydrophobic thiol compound, N-acetyl cysteine proline cysteine amide (CB3), in allergic airway diseases. METHODS: We used ovalbumin (OVA)-inhaled mice to evaluate the role of CB3 as an antiinflammatory reagent and to determine its molecular signaling activity in allergic airways. MEASUREMENTS AND MAIN RESULTS: The administration of CB3 (1-50 mg/kg) to OVA-inhaled mice restored the decreased GSH levels, enhanced IL-10 expression, and significantly reduced the increase of Th2 cytokines and OVA-specific IgE. CB3 decreased the number of inflammatory cells and airway hyperresponsiveness in the lungs. We also found that the administration of CB3 dramatically decreased the nuclear translocation of the nuclear factor-κB (NF-κB) and the phosphorylation of p38 mitogen-activated protein kinases (MAPKs) in lungs after OVA inhalation. In addition, allergen-induced airway inflammation and hyperresponsiveness were substantially reduced by the administration of inhibitors of NF-κB and p38 MAPK, BAY 11-7085, and SB 239063, respectively. CONCLUSIONS: These results suggest that CB3 attenuates allergic airway disease by up-regulation of GSH levels as well as inhibition of NF-κB and p38 MAPK activity.

Melampolides from the leaves of Smallanthus sonchifolius and their inhibitory activity of lps-induced nitric oxide production.

Two new melampolide-type sesquiterpene lactones, 8beta-epoxyangeloyloxy-9alpha-ethoxy-14-oxo-acanthospermolide (1) and 8beta-angeloyloxy-9alpha-ethoxy-14-oxo-acanthospermolide (2), were isolated from the leaves of yacon [Smallanthus sonchifolia (POEPP. et ENDL.) H. Robinson] along with eleven known melampolides, allo-schkuhriolide (3), enhydrin (4), polymatin A (5), fluctuanin (6), 8beta-angeloyloxy-9alpha-acetoxy-14-oxo-acanthospermolide (7), 8beta-angeloyloxy-14-oxo-acanthospermolide (8), 8beta-methacryloyloxymelampolid-14-oic acid methyl ester (9), uvedalin (10), polymatin B (11), 8beta-tigloyloxymelampolid-14-oic acid methyl ester (12), and sonchifolin (13). Their structures were established on the basis of spectroscopic evidence including 1D- and 2D-NMR experiments. All isolates were evaluated for inhibition of LPS-induced nitric oxide production in murine macrophage RAW 264.7 cells.

Monoamine oxidase inhibitory constituents from the fruits of Cudrania tricuspidata.

A methylene chloride soluble fraction of the fruits of Cudrania tricuspidata significantly inhibited the mouse brain monoamine oxidase (MAO). Three known prenylated isoflavones were isolated and identified by activity-guided fractionation. Gancaonin A (1), 4'-O-methylalpinumisoflavone (2), and alpinumisoflavone (3) inhibited MAO activity in a concentration-dependent manner with IC50 values of 19.4, 23.9, and 25.8 microM, respectively. Of these, gancaonin A (1) showed a selective and potent inhibitory effect against MAO-B (IC50 0.8 microM) than MAO-A (IC50 >800 microM). The kinetic analysis using Lineweaver-Burk plots indicated that gancaonin A (1) competitively inhibited MAO-B.