Non-invasive transcranial ultrasound stimulation for neuromodulation.

Transcranial ultrasound stimulation (TUS) holds great potential as a tool to alter neural circuits non-invasively in both animals and humans. In contrast to established non-invasive brain stimulation methods, ultrasonic waves can be focused on both cortical and deep brain targets with the unprecedented spatial resolution as small as a few cubic millimeters. This focusing allows exclusive targeting of small subcortical structures, previously accessible only by invasive deep brain stimulation devices. The neuromodulatory effects of TUS are likely derived from the kinetic interaction of the ultrasound waves with neuronal membranes and their constitutive mechanosensitive ion channels, to produce short term and long-lasting changes in neuronal excitability and spontaneous firing rate. After decades of mechanistic and safety investigation, the technique has finally come of age, and an increasing number of human TUS studies are expected. Given its excellent compatibility with non-invasive brain mapping techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), as well as neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), systemic TUS effects can readily be assessed in both basic and clinical research. In this review, we present the fundamentals of TUS for a broader audience. We provide up-to-date information on the physical and neurophysiological mechanisms of TUS, available readouts for its neural and behavioral effects, insights gained from animal models and human studies, potential clinical applications, and safety considerations. Moreover, we discuss the indirect effects of TUS on the nervous system through peripheral co-stimulation and how these confounding factors can be mitigated by proper control conditions.

Outcomes of standard and tailored anti-tuberculosis regimens in patients with tuberculous pleural effusion.

BACKGROUND: In an era of increasing concerns about drug resistance, there are limited data on treatment outcomes and recurrence rates after standard short-course anti-tuberculosis treatment in patients with culture-negative tuberculous pleural effusion (TPE). OBJECTIVE: To compare treatment outcomes and recurrence rates between a standard anti-tuberculosis regimen with negative culture and unavailable drug susceptibility testing (DST) data, and a tailored anti-tuberculosis regimen based on individual DST data. DESIGN: We analysed the data of all patients with TPE from the TB registry database at Kyungpook National University Hospital, South Korea, during 2008-2012. The study population was divided into two groups according to regimen. RESULTS: Standard and tailored anti-tuberculosis regimens were administered to respectively 124 and 146 patients with TPE. Drug resistance was detected in 10% of patients with TPE, about a quarter of whom were multidrug-resistant. The treatment completion rate was not significantly different between the two groups (91% vs. 93%). During a median 20-month follow-up, the recurrence rate was also similar in both groups (1% vs.1%). CONCLUSIONS: Despite limited statistical power, these preliminary results support the hypothesis that immunocompetent patients with culture-negative TPE can be appropriately managed with a standard short-course anti-tuberculosis regimen, even in this era of increasing concerns about drug resistance.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Radiologic and laboratory differences in patients with tuberculous and parapneumonic pleural effusions showing non-lymphocytic predominance and high adenosine deaminase levels.

PURPOSE: Tuberculous pleural effusion (TPE) is characterized by lymphocytic predominance and high adenosine deaminase (ADA) levels. However, TPEs sometimes present non-lymphocytic predominance, and parapneumonic effusion (PPE) often exceeds the cutoff value of ADA for TPE. Thus, the differential diagnosis of cases with pleural fluid (PF) showing non-lymphocytic predominance and high ADA levels is challenging. However, limited data concerning the clinical differences in these patients are available. METHODS: A retrospective study was conducted on TPE and PPE patients with PF showing non-lymphocytic predominance and ADA levels ≥40 U/L in 2009-2013 in a South Korean tertiary referral hospital. The clinical, laboratory, and computed tomography (CT) findings between the groups were analyzed using multivariate logistic regression to develop a prediction model with independent factors for TPE. RESULTS: Among 353 patients with TPE, 24 (6.8 %) showed PF with non-lymphocytic predominance and ADA levels of ≥40 U/L. Twenty-eight PPE patients who presented PF findings comparable with those of TPE patients were included in the control group. In the final analysis, PF ADA levels >58 U/L and nodular lung lesions on CT were independent positive predictors, while loculated effusion was an independent negative predictor for TPE. Using the prediction model, a score ≥ +3 provided a sensitivity of 88 %, specificity of 93 %, positive predictive value of 91 %, and negative predictive value of 90 % for TPE. CONCLUSION: PF ADA levels, nodular lung lesions, and loculated pleural effusion may help differentiate TPE from PPE in patients with PF showing non-lymphocytic predominance and ADA levels ≥40 U/L.

Comparison of the incidence between tuberculosis and nontuberculous mycobacterial disease after gastrectomy.

PURPOSE: Gastrectomy is a well-known risk factor for tuberculosis (TB). However, little data are available regarding the relationship between gastrectomy and the risk of nontuberculous mycobacterial (NTM) disease. Here, we investigated the incidence of TB and NTM lung disease in gastrectomized patients. METHOD: New cases of TB and NTM lung infection or disease were examined among patients who had undergone gastrectomy due to gastric cancer from 2003 to 2009 at a tertiary referral hospital in South Korea. Annualized incidence rates for cases were compared with those of the general population. RESULTS: This study included a total of 2,684 patients. New mycobacterial cases were found in 41 patients. Cases of TB and NTM lung infection were 35 (85 %) and 6 (15 %) including 2 NTM lung disease cases, respectively. Annualized crude incidence rates for TB, NTM lung infection, and NTM lung disease were 327/100,000, 56/100,000, and 19/100,000, respectively. The age-standardized incidence rate of TB was significantly higher in gastrectomized patients than in the general population. However, the standardized incidences of NTM lung infection and disease were not significantly different from those of non-gastrectomized patients. Patients with NTM lung infection frequently exhibited comorbid chronic lung disease, while those with TB were more frequently found to have fibronodular lesions on preoperative chest radiography. CONCLUSIONS: Gastrectomy does not appear to increase the risk of NTM lung disease. However, NTM lung infection or disease should be considered as a differential diagnosis of pulmonary TB in gastrectomized patients accompanying chronic lung disease.

Transient thyrotoxicosis from thyroiditis induced by sibutramine overdose: a case report.

Sibutramine is an antiobesity drug that inhibits the reuptake of serotonin and noradrenalin in the hypothalamus. A 37-year-old Korean man presented to the emergency room for the oral intake of 280 mg of sibutramine. The patient was in thyrotoxic state. The (99m)Technetium-pertechnetate thyroid scan showed irregular uptake of radioisotope and thyroid-stimulating hormone receptor antibody and thyroperoxidase antibody were negative. Thyroid function normalized after that. The patient had transient thyrotoxicosis with thyroiditis. We report a case of thyrotoxicosis accompanied by thyroiditis resulting from the intentional overdose of sibutramine.

Accelerated resolution of laser-induced bruising with topical 20% arnica: a rater-blinded randomized controlled trial.

BACKGROUND: Dermatological procedures can result in disfiguring bruises that resolve slowly. OBJECTIVES: To assess the comparative utility of topical formulations in hastening the resolution of skin bruising. METHODS: Healthy volunteers, age range 21-65 years, were enrolled for this double (patient and rater) blinded randomized controlled trial. For each subject, four standard bruises of 7 mm diameter each were created on the bilateral upper inner arms, 5 cm apart, two per arm, using a 595-nm pulsed-dye laser (Vbeam; Candela Corp., Wayland, MA, U.S.A.). Randomization was used to assign one topical agent (5% vitamin K, 1% vitamin K and 0·3% retinol, 20% arnica, or white petrolatum) to exactly one bruise per subject, which was then treated under occlusion twice a day for 2 weeks. A dermatologist not involved with subject assignment rated bruises [visual analogue scale, 0 (least)-10 (most)] in standardized photographs immediately after bruise creation and at week 2. RESULTS: There was significant difference in the change in the rater bruising score associated with the four treatments (anova, P=0·016). Pairwise comparisons indicated that the mean improvement associated with 20% arnica was greater than with white petrolatum (P=0·003), and the improvement with arnica was greater than with the mixture of 1% vitamin K and 0·3% retinol (P=0·01). Improvement with arnica was not greater than with 5% vitamin K cream, however. CONCLUSIONS: Topical 20% arnica ointment may be able to reduce bruising more effectively than placebo and more effectively than low-concentration vitamin K formulations, such as 1% vitamin K with 0·3% retinol.

Physicochemical properties, and antioxidant and antimicrobial effects of garlic and onion powder in fresh pork belly and loin during refrigerated storage.

Pork loin and belly cuts were pumped to 110% of their original weight with solutions containing 5% of various ingredients (sodium ascorbate, garlic, and onion powder), and evaluated the physicochemical properties, and antioxidant and antimicrobial activities during refrigerated storage at 8 degrees C. The addition of garlic and onion powder tended to increase redness (a) and yellowness (b) in both the belly lean and loin with the exception of a few cases. Free fatty acid values in both pork belly and loin cuts were reduced with the addition of these ingredients, as compared to the control. Significant differences in peroxide values were observed in sodium ascorbate and garlic-injected belly, and in sodium ascorbate and onion-injected loin, as compared to the control. Thiobarbituric acid reactive substance values in the pork belly with garlic or onion powder were significantly lower than in the belly without these ingredients or with sodium ascorbate (P < 0.05). Total plate counts were lower in both the belly and loin containing garlic and onion powder, as compared to the control. In both the belly and loin cuts, the content of oxidative products (volatile compounds) was reduced with the addition of garlic and onion powder, particularly the aldehydes (hexanal). Overall, garlic and onion in enhanced meats showed an antioxidant activity as effective as that of sodium ascorbate and also an antimicrobial effect to inhibit the growth of total bacteria and Enterobacteriaceae.

Effects of pork meat cut and packaging type on lipid oxidation and oxidative products during refrigerated storage (8 degrees C).

Lipid oxidation and oxidative products as affected by pork meat cut, packaging method, and storage time were evaluated during refrigerated storage. Pork belly had higher pH and thiobarbituric acid reactive substance (TBARS) values than pork loin, and aerobic-packaged belly had higher TBARS than vacuum-packaged counterparts. Loin had higher free fatty acid (FFA) values than belly, and increased FFA values were observed with increased storage time. Peroxide values increased up to 7 d and decreased thereafter. Volatile compounds such as alkanes, aldehydes, ketones, and alcohols with high volatility in belly were higher than those in loin. Nonanoic acid, ethyl ester in belly, and hexadecanoic acid in loin might be considered as indices of lipid oxidation. Overall, vacuum packaging was better than aerobic packaging to retard lipid oxidation and production of oxidative products, and loin was more sensitive to lipid oxidation than belly.

Evaluation of lipid oxidation and oxidative products as affected by pork meat cut, packaging method, and storage time during frozen storage (-10 degrees C).

Lipid oxidation and oxidative volatiles as affected by pork meat cut and packaging method during frozen storage at -10 degrees C were evaluated. Pork belly cut had higher thiobarbituric acid reactive substance (TBARS) and pH values than did the loin, whereas the loin had higher free fatty acid (FFA) values than that of the belly cut. Peroxide values increased with increased storage time, but were not affected by pork meat cut and packaging method. Volatiles with carbon numbers less than 10 in the belly cut were higher than those in the loin cut, whereas those with carbon numbers greater than 10 in the loin cut were higher than those in belly cut. Most volatiles were decreased with increased storage time, except for propane. Both 4-pentenal and 4-methyl-2-hexanone in the belly cut showed a positive correlation with FFA, whereas 2,4-dimethyl-1-heptene and 9-octadecenal in the loin cut were positively correlated with TBARS and FFA, respectively, even though the values were not high enough to predict the degree of lipid oxidation.

Abnormal thalamic volume in treatment-naïve boys with Tourette syndrome.

OBJECTIVE: Thalamic abnormality has been implicated in the pathophysiology of Tourette's syndrome (TS). We examined the presence of aberrant thalamic volume from the treatment-naïve boys with TS using magnetic resonance imaging (MRI). METHOD: Volumetric MRI was performed on 18 treatment-naïve boys with TS, aged 7-14 years, and 16 healthy comparison subjects. The anatomical boundaries were then manually parcellated to measure the thalamic volume. RESULTS: Tourette's syndrome subjects had a significantly larger left thalamus in comparison with those of healthy subjects. On the contrary, no group difference was observed from the right thalamic volume. TS subjects also showed a significant reduction in rightward asymmetry in thalamic volume compared with the healthy subjects. CONCLUSION: Our findings provide new evidence of abnormal thalamic volume in pediatric TS.

Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase.

AIMS/HYPOTHESES: Type I (insulin-dependent) diabetes mellitus results from T-cell-mediated autoimmune destruction of pancreatic beta cells. Among the beta-cell autoantigens that have been implicated in triggering of beta-cell-specific autoimmunity, glutamic acid decarboxylase (GAD) is a strong candidate in both humans and the NOD mouse. We aimed to determine whether treatment with a recombinant vaccinia virus expressing GAD (rVV-GAD65) could prevent the development of diabetes in NOD mice. METHODS: Three-eight-to-nine-week-old female NOD mice were injected with various doses of rVV-GAD65 or rVV-MJ601as a control. We then examined the incidence of diabetes, T-cell proliferative response to GAD, amounts of anti-GAD IgGs, cytokine production and generation of regulatory cell populations. RESULTS: Administration of rVV-GAD65 to NOD mice prevented diabetes in an age-dependent and dose-dependent manner. Splenic T cells from rVV-GAD65-treated mice did not proliferate in response to GAD65. The amount of IgG1 was increased, whereas IgG2a amounts did not change in rVV-GAD65-treated NOD mice. The production of interleukin-4 increased, whereas the production of interferon-gamma decreased in rVV-GAD65-treated mice after stimulation with GAD. Furthermore, splenocytes from rVV-GAD65-treated NOD mice prevented the transfer of diabetes by splenocytes from acutely diabetic NOD mice in NOD. scid recipients. CONCLUSION/INTERPRETATION: Immunogene therapy using a recombinant vaccinia virus expressing GAD results in the prevention of autoimmune diabetes in NOD mice by the induction of immunological tolerance through active suppression of effector T cells, and this treatment might have therapeutic value for the prevention of Type I diabetes.

Multiresolution data acquisition and detection in functional MRI.

In an investigation of a multiresolution and multistaged approach in functional MRI, the relationship between spatial resolution and detection of functional activation is examined. The difference between functional detection and mapping is defined, and a multiresolution approach to functional detection is analyzed by constructing simple theoretical and experimental models simulating variations of in-plane resolution. Experimentally measured blood oxygenation level-dependent (BOLD) signal changes as well as BOLD contrast-to-noise ratio (CNR) with respect to different spatial resolutions are compared with results from theoretical predictions and simulation. From both an experimental and a theoretical perspective, it is shown that BOLD CNR and, thus, the concomitant detection of the functional activation are maximized when the resolution matches the size of activation.

Interactive 3-dimensional segmentation of MRI data in personal computer environment.

We describe a method of interactive three-dimensional segmentation and visualization for anatomical magnetic resonance imaging (MRI) data in a personal computer environment. The visual feedback necessary during 3-D segmentation was provided by a ray casting algorithm, which was designed to allow users to interactively decide the visualization quality depending on the task-requirement. Structures such as gray matter, white matter, and facial skin from T1-weighted high-resolution MRI data were segmented and later visualized with surface rendering. Personal computers with central processing unit (CPU) speeds of 266, 400, and 700 MHz, were used for the implementation. The 3-D visualization upon each execution of the segmentation operation was achieved in the order of 2 s with a 700 MHz CPU. Our results suggest that 3-D volume segmentation with semi real-time visual feedback could be effectively implemented in a PC environment without the need for dedicated graphics processing hardware.

Human brain mapping of auditory imagery: event-related functional MRI study.

We used event-related fMRI methodology to investigate human brain activity during auditory imagery. A series of susceptibility-weighted MR images covering the whole brain were acquired to obtain blood oxygenation level-dependent (BOLD) signal changes associated with the imagery event of hearing simple monotone. Group analysis across the 12 right-handed subjects revealed activations in the medial and inferior frontal gyri, precuneus, middle frontal gyri, superior temporal gyri, and anterior cingulate gyri. Bilateral primary and secondary auditory areas in the superior temporal gyri also exhibited the event-related MR signal changes. The proposed method allowed for the analysis of brain areas responsive to the event of auditory imagery while our results suggest that auditory imagery and actual audition share common neural substrates.

Hemodynamic effects on atherosclerosis-prone coronary artery: wall shear stress/rate distribution and impedance phase angle in coronary and aortic circulation.

The objective of the present study was to evaluate the hemodynamic characteristics of an atherosclerosis-prone coronary artery compared to the aorta. We describe three- dimensional spatial patterns of wall shear stress (WSS) according to the impedance phase angle in pulsatile coronary and aorta models using in vivo hemodynamic parameters and computed numerical simulations both qualitatively and quantitatively. Angiography of coronary arteries and aortas were done to obtain a standard model of vascular geometry. Simultaneously to the physiologic studies, flow-velocity and pressure profiles from in vivo data of the intravascular Doppler and pressure wire studies allowed us to include in vitro numerical simulations. Hemodynamic variables, such as flow-velocity, pressure and WSS in the coronary and aorta models were calculated taking into account the effects of vessel compliance and phase angle between pressure and flow waveforms. We found that there were spatial fluctuations of WSS and in the recirculation areas at the curved outer wall surface of the coronary artery. The mean WSS of the calculated negative phase angle increased in the coronary artery model over that in the aorta model and the phase angle effect was most prominent on the calculated amplitude of WSS of the coronary artery. This study suggests that the rheologic property of coronary circulation, such as the fluctuation of WSS/WSR induces several hemodynamic characteristics. A separation of flow-velocity, a difference in phase between pressure conductance and blood flow and prominent temporal and/or spatial oscillatory fluctuations of the shear forces as a function of pulsatile flow might be important factors in atherogenesis and progression of atherosclerosis.

A functional magnetic resonance imaging study of auditory mismatch in schizophrenia.

OBJECTIVE: Previous research has noted functional and structural temporal lobe abnormalities in schizophrenia that relate to symptoms such as auditory hallucinations and thought disorder. The goal of the study was to determine whether the functional abnormalities are present in schizophrenia at early stages of auditory processing. METHOD: Functional magnetic resonance imaging activity was examined during the presentation of the mismatch stimuli, which are deviant tones embedded in a series of standard tones. The mismatch stimuli are used to elicit the mismatch negativity, an early auditory event-related potential. Ten patients with schizophrenia and 10 comparison subjects were presented the mismatch stimuli condition and a control condition in which only one tone was presented repeatedly. RESULTS: The superior temporal gyrus showed the most prevalent and consistent activation. The superior temporal gyrus showed less activation in the schizophrenic subjects than in the comparison subjects only during the mismatch stimuli condition. CONCLUSIONS: This result is consistent with those of mismatch negativity event-related potential studies and suggests that early auditory processing is abnormal in chronic schizophrenia.

Prognostic significance of cyclin D1 protein levels in early-stage larynx cancer treated with primary radiation.

Recent laboratory experiments have demonstrated that cyclin D1 levels (cycD1) can influence radiosensitivity. The purpose of the current study is to evaluate the prognostic significance of cycD1 for local recurrence in early-stage larynx cancer treated with primary radiation therapy. The study was conducted using a matched case-control design in 60 early-stage (T1-T2/N0) larynx cancer patients. All patients had squamous cell carcinoma of the larynx and were treated with primary radiation to a total median dose of 66 Gy in daily fractions of 2 Gy, without surgery or chemotherapy. Thirty patients who suffered a local relapse in the larynx after treatment served as the index case population. These 30 cases were matched by age, sex, site (glottic vs. supraglottic), radiation therapy technique/dose, and follow-up, to 30 control patients who did not experience a local relapse. Immunohistochemical staining from cycD1 was performed on the paraffin-embedded specimens. The pathologist, blinded to the clinical information, scored each of the specimens on a four-point intensity scale (0 = no stain, 1 = faint, 2 = moderate, 3 = strong) and percent distribution. Patients were considered to be positive for cyclin D1 if the staining was 2+ or greater with a percent distribution of at least 5%. By design of the study, the two groups were evenly balanced with respect to age, sex, stage, radiation dose, and follow-up. CycD1 levels correlated with proliferating cell nuclear antigen levels. Low levels of cycD1 significantly correlated with local relapse; 19/30 (63%) of the index cases stained negative, while only 10/30 (33%) of the control cases stained negative (P = 0.03). These data suggest that low levels of cycD1 correlate with relatively radioresistant early-stage larynx carcinoma. With larger more confirmatory clinical and laboratory data, this data may have significant clinical implications. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 22-28 (2000).

Transglycosylation of neohesperidin dihydrochalcone by Bacillus stearothermophilus maltogenic amylase.

Neohesperidin dihydrochalcone (NHDC), a sweet compound derived from citrus fruits, was modified to a series of its oligosaccharides by transglycosylation activity of Bacillus stearothermophilus maltogenic amylase (BSMA). Maltotriose as a donor was reacted with NHDC as an acceptor to glycosylate for the purpose of increasing the solubility of NHDC. Maltosyl-NHDC was a major transglycosylation product among the several transfer products by TLC analysis. The structure of the major transglycosylation product was determined to be maltosyl-alpha-(1,6)-neohesperidin dihydrochalcone by MALDI-TOF/MS and (1)H and (13)C NMR. Maltosyl-NHDC was 700 times more soluble in water and 7 times less sweet than NHDC.