MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways.
Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domain-containing protein-mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170)--is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wild-type MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.


Cellular and synaptic adaptations mediating opioid dependence.
Although opioids are highly effective for the treatment of pain, they are also known to be intensely addictive. There has been a massive research investment in the development of opioid analgesics, resulting in a plethora of compounds with varying affinity and efficacy at all the known opioid receptor subtypes. Although compounds of extremely high potency have been produced, the problem of tolerance to and dependence on these agonists persists. This review centers on the adaptive changes in cellular and synaptic function induced by chronic morphine treatment. The initial steps of opioid action are mediated through the activation of G protein-linked receptors. As is true for all G protein-linked receptors, opioid receptors activate and regulate multiple second messenger pathways associated with effector coupling, receptor trafficking, and nuclear signaling. These events are critical for understanding the early events leading to nonassociative tolerance and dependence. Equally important are associative and network changes that affect neurons that do not have opioid receptors but that are indirectly altered by opioid-sensitive cells. Finally, opioids and other drugs of abuse have some common cellular and anatomical pathways. The characterization of common pathways affected by different drugs, particularly after repeated treatment, is important in the understanding of drug abuse.


Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of Trypanosoma cruzi Infection.
Chagas cardiomyopathy is caused by Trypanosoma cruzi (Tc). We identified two candidate antigens (TcG2 and TcG4) that elicit antibodies and T cell responses in naturally infected diverse hosts. In this study, we cloned TcG2 and TcG4 in a nanovector and evaluated whether nano-immunotherapy (referred as nano2/4) offers resistance to chronic Chagas disease. For this, C57BL/6 mice were infected with Tc and given nano2/4 at 21 and 42 days post-infection (pi). Non-infected, infected, and infected mice treated with pcDNA3.1 expression plasmid encoding TcG2/TcG4 (referred as p2/4) were used as controls. All mice responded to Tc infection with expansion and functional activation of splenic lymphocytes. Flow cytometry showed that frequency of splenic, poly-functional CD4+ and CD8+ T cells expressing interferon-γ, perforin, and granzyme B were increased by immunotherapy (Tc.nano2/4 > Tc.p2/4) and associated with 88%-99.7% decline in cardiac and skeletal (SK) tissue levels of parasite burden (Tc.nano2/4 > Tc.p2/4) in Chagas mice. Subsequently, Tc.nano2/4 mice exhibited a significant decline in peripheral and tissues levels of oxidative stress (e.g., 4-hydroxynonenal, protein carbonyls) and inflammatory infiltrate that otherwise were pronounced in Chagas mice. Further, nano2/4 therapy was effective in controlling the tissue infiltration of pro-fibrotic macrophages and established a balanced environment controlling the expression of collagens, metalloproteinases, and other markers of cardiomyopathy and improving the expression of Myh7 (encodes β myosin heavy chain) and Gsk3b (encodes glycogen synthase kinase 3) required for maintaining cardiac contractility in Chagas heart. We conclude that nano2/4 enhances the systemic T cell immunity that improves the host's ability to control chronic parasite persistence and Chagas cardiomyopathy.


Hierarchical porous Ni@boehmite/nickel aluminum oxide flakes with enhanced microwave absorption ability.
In this article, composites consisting of porous Ni cores coated with boehmite/nickel aluminum oxide nanoflakes were successfully prepared by a versatile method. The crystal constituents and shapes of the boehmite/nickel aluminum oxide nanoflakes were strongly influenced by reaction temperature, and their microwave absorption properties were investigated in terms of complex permittivity and permeability. The results reveal that the composites comprising porous Ni cores coated with boehmite/nickel aluminum oxide synthesized at 180 °C present superior absorption properties. The optimal reflection loss is -44.3 dB (>99.99% attenuation) at 14.4 GHz, and the effective absorption (below -10 dB) bandwidth can be monitored in the frequency range of 5.8-18.0 GHz for an absorber with thickness in the range of 1.5-3.5 mm. The high dissipation capability, good impedance match and multiple reflection of the porous flaky structure are responsible for the improvement in microwave absorption. Moreover, a new absorption mechanism was proposed for the porous structure. In this mechanism, the porous structure serves as a spreading container, which attenuates electromagnetic energy by prolonging the travel path and constrains waves in the void space to gradually consume energy. This method paves a new avenue to design porous magnetic-dielectric absorbing materials.


Quality of life and post-concussion symptoms in adults after mild traumatic brain injury: a population-based study in western Sweden.
To study quality of life and subjective post-concussion symptoms in adults (16-60 years) with a mild traumatic brain injury (MTBI) 3 months and 1 year after injury. Of a total of 489 patients 173 responded to questionnaires at 3 months and at 1 year, including the SF-36 health-related quality of life survey, which is a standardized measure validated for Swedish conditions. Post-concussion symptoms were rated as either existing or non-existing in a 21-item checklist [a modified version of Comprehensive Psychopathological Rating Scale (CPRS)]. SF-36 showed impaired scores in all dimensions. Existing post-concussion symptoms were reported by 1545%. Significantly, more symptoms were present at 3 months than at 3 weeks after injury. Furthermore, a significant correlation between higher rates of post-concussion symptoms and lower SF-36 scores was found. The SF-36 results were significantly impaired compared with an age- and gender-matched normative control group and the rate of post-concussion symptoms was significantly higher at 3 months than at 3 weeks after injury. As a significant correlation between higher rates of symptoms and low SF-36 scores was also found we assume SF-36 to be a sensitive enough measure of MTBI-related effects.


Nanoconfinement greatly speeds up the nucleation and the annealing in single-DNA collapse.
Manipulating and measuring single-molecule dynamics and reactions in nanofluidics is a rapidly growing field with broad applications in developing new biotechnologies, understanding nanoconfinement effects in vivo, and exploring new phenomena in confinement. In this work, we investigate the kinetics of DNA collapse in nanoslits using single T4-DNA (165.6 kbp) and λ-DNA (48.5 kbp), with particular focus on the measurement of the nucleation and annealing times. Fixing the ethanol concentration at 35% and varying the slit height from 2000 to 31 nm, the nucleation time dramatically decreases from more than 1 hour to a few minutes or less. The increased collapsed rate results from the larger free energy experienced by coiled DNA in confinement relative to compacted DNA. Our results also shed light on other conformational transitions in confinement, such as protein folding.


Dynamic thermal structure of imported fire ant mounds.
A study was undertaken to characterize surface temperatures of mounds of imported fire ant, Solenopsis invicta Buren (Hymenoptera: Formicidae) and S. richteri Forel, and their hybrid, as it relates to sun position and shape of the mounds, to better understand factors that affect absorption of solar radiation by the nest mound and to test feasibility of using thermal infrared imagery to remotely sense mounds. Mean mound surface temperature peaked shortly after solar noon and exceeded mean surface temperature of the surrounding surface. Temperature range for mounds and their surroundings peaked near solar noon, and the temperature range of the mound surface exceeded that of the surrounding area. The temperature difference between mounds and their surroundings peaked around solar noon and ranged from about 2 to 10 degrees C. Quadratic trends relating temperature measurements to time of day (expressed as percentage of daylight hours from apparent sunrise to apparent sunset) explained 77 to 88% of the variation in the data. Mounds were asymmetrical, with the apex offset on average 81.5 +/- 1.2 mm to the north of the average center. South facing aspects were about 20% larger than north facing aspects. Mound surface aspect and slope affected surface temperature; this affect was greatly influenced by time of day. Thermal infrared imagery was used to illustrate the effect of mound shape on surface temperature. These results indicate that the temperature differences between mounds and their surroundings are sufficient for detection using thermal infrared remote sensing, and predictable temporal changes in surface temperature may be useful for classifying mounds in images.


On-line adaptive algorithm with glucose prediction capacity for subcutaneous closed loop control of glucose: evaluation under fasting conditions in patients with Type 1 diabetes.
To evaluate an algorithm with glucose prediction capacity and continuous adaptation of patient parameters-a model predictive control (MPC) algorithm-to control blood glucose concentration during fasting conditions in patients with Type 1 diabetes. In the subcutaneous (sc) route within a closed loop system. Paired experiments were performed in six patients. Over 8 h the MPC algorithm was used to control glucose with s.c. insulin administration and two different glucose monitoring protocols: first, the algorithm was provided with intravenous (i.v.) glucose values for insulin dosage calculation directly (i.v.-s.c. route). Then, in the second experiment, i.v. glucose values were fed to the MPC with a delay of 30 min to simulate s.c. glucose measurements ('s.c.'-s.c. route). In both experiments plasma glucose, insulin dosage, and serum insulin levels were analysed. Glucose concentration was brought from hyper- to normoglycaemia and kept in the physiological range (6-7 mmol/l) with both routes in all subjects. Mean glucose concentration reached the threshold of 7 mmol/l approximately 2 (i.v.-s.c. route) and 3 ('s.c.'-s.c. route) hours after the start of glucose control with the MPC. During the last 2 h of automated glucose control, mean glucose concentration was 6.3 +/- 0.2 mmol/l and 6.6 +/- 0.3 mmol/l for i.v.-s.c. and 's.c.'-s.c. route, respectively. Glucose concentration, insulin doses, and serum insulin levels did not differ significantly between routes (P > 0.05). The MPC algorithm is suitable for glucose control during fasting within an extracorporeal artificial beta-cell in the subcutaneous route Type 1 diabetic patients.


Parental Smoking and Smoking Cognitions among Youth: A Systematic Review of the Literature.
We summarized and discussed the empirical evidence for an association between parental smoking and smoking-related cognitions among youth and for the mediating role of smoking-related cognitions in the relation between parental and youth smoking behaviour. We conducted a systematic review of articles published between 1980 and February 2015 using the databases PsychInfo and PubMed. The systematic search resulted in 41 eligible studies. Only 4 studies investigated smoking-related cognitions as putative mediators in the association between parental and youth smoking. The synthesis of evidence showed a mix of significant and non-significant associations between parental smoking and smoking-related cognitions among youth. A majority of results reported positive associations even when non-significant findings were found. However, studies that report an effect suggest that the effect may be quite modest. Empirical evidence does not confirm the commonly applied assertions of social learning theories that parental smoking increases the risk of youth smoking through the development of favourable smoking-related cognitions. Methodological and theoretical aspects that might explain the lack of consistent findings are discussed.


Yonsei criteria: a clinical reflection of stage I left-sided pancreatic cancer.
In this study, we examined associations between pancreatic cancer that met the Yonsei criteria (YC) and classifications from the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. Clinicopathological and survival data were collected from132 patients who underwent distal pancreatectomy for left-sided pancreatic ductal adenocarcinoma between January 2000 and December 2015, and the utility of the YC for selecting treatment and predicting survival was evaluated using the 8th AJCC staging manual. Of the 102 patients who ultimately qualified for the study, 45 patients were reclassified as stage I based on the 8th AJCC cancer staging system. Disease-free survival and disease-specific survival periods were longer in stage I patients who met the YC than in those who did not. Clinicopathological characteristics did not differ between stage I patients who did and did not meet the YC. These results suggest that meeting the YC criteria may be a clinical indicator that left-sided pancreatic cancer patients who are candidates for resection have early-stage disease according to the 8th edition of the AJCC staging manual.


Developing an efficient protocol for monitoring eagle fatalities at wind energy facilities.
Researchers typically conduct fatality monitoring to determine a wind energy facility's direct impacts on wildlife. In the United States, wind energy impacts on eagles have received increased attention in recent years because eagle incidental take permits became available. Permit holders are required to conduct fatality monitoring to evaluate compliance with permitted eagle take. Our objective was to develop an efficient eagle fatality monitoring protocol with a quantifiable detection probability based on a stationary scanning search method. We conducted scanning searches for eagle carcasses at four wind energy facilities. We estimated searcher efficiency of the scanning search method using feathered turkey decoys as eagle carcass surrogates, used publicly available data on large raptor carcass distances from turbines to evaluate the proportion of carcasses expected to occur in searched areas, and estimated carcass persistence rates for game birds and raptors. These three bias adjustments were combined to estimate the overall probability of detection for the scanning search method. We found generally high searcher efficiency for the scanning search method, with 76% of decoys detected; however, detection decreased with distance and difficulty of visibility class. Mean carcass persistence time varied between 28 and 76 days for raptors and between three and nine days for game birds, showing that game birds do not persist as long as raptors. We estimated that 95% of large avian carcasses fall within 100 m of turbine bases, and 99% fall within 150 m. Using these estimates and assuming a 30-day search interval for all facility turbines, we estimated that the probability of detecting a large raptor carcass using the scanning search method at a wind facility ranged from 0.50 to 0.69. Our research suggests a monitoring program that uses scanning searches can be a cost-effective approach for gathering data necessary to meet incidental eagle take permit requirements.


Anesthetics significantly increase the amount of intramembrane water in lipid membranes.
The potency of anesthesia was directly linked to the partitioning of the drug molecules in cell membranes by Meyer and Overton. Many molecules interact with lipid bilayers and lead to structural and functional changes. It remains an open question which change in membrane properties is responsible for a potential anesthetic effect or if anesthetics act by binding to direct targets. We studied the effect of ethanol, diethyl ether and isoflurane on the water distribution in lipid bilayers by combining all-atom molecular dynamics simulations and neutron diffraction experiments. The simulations show strong membrane-drug interactions with partitioning coefficients of 38%, 92% and 100% for ethanol, diethyl ether and isoflurane, respectively, and provide evidence for an increased water partitioning in the membrane core. The amount of intramembrane water molecules was experimentally determined by selectively deuterium labeling lipids, anesthetic drug and water molecules in neutron diffraction experiments. Four additional water molecules per lipid were observed in the presence of ethanol. Diethyl ether and isoflurane were found to significantly increase the amount of intramembrane water by 25% (8 water molecules). This increase in intramembrane water may contribute to the non-specific interactions between anesthetics and lipid membranes.


New Cu(i) halide complexes showing TADF combined with room temperature phosphorescence: the balance tuned by halogens.
A series of Cu(i) halide complexes derived from tris(2-pyridyl)phosphine (Py3P), [Cu2(Py3P)2X2] (X = Cl, Br, I), have been synthesized by a straightforward reaction in solution or through a mechanochemical route. At room temperature, the solid complexes exhibit bright dual-mode photoluminescence (λmax = 520-550 nm, τ = 14.5-20.0 μs, and ΦPL ≈ 53%), expressed by thermally activated delayed fluorescence (TADF) combined with phosphorescence (PH), originating from 1(M + X)LCT and 3(M + X)LCT excited states, respectively. Remarkably, the balance of these radiative processes at 300 K is regulated by halogen atom nature, switching from TADF-assisted phosphorescence to PH-admixed TADF. The emission of [Cu2(Py3P)2Cl2] at 300 K is largely contributed by PH (73%) admixed with the TADF fraction (27%) and [Cu2(Py3P)2Br2] also emits mainly PH (65%) admixed with the larger TADF fraction (35%). Meanwhile, for [Cu2(Py3P)2I2], the TADF channel becomes dominating (61%) and PH contribution drops to 39%. The photophysical study corroborated by (TD)DFT computations has revealed that this effect arises mainly from the narrowing of the ΔE(S1 - T1) gap of the [Cu2(Py3P)2X2] complexes in the order Cl (1500 cm-1) > Br (1250 cm-1) > I (1000 cm-1) which facilitates the TADF pathway and suppresses PH in the same order.


Assessing positive and negative symptoms in outpatients with schizophrenia and mood disorders.
The Positive and Negative Syndrome Scale (PANSS) was developed to assess symptomatology in inpatients with schizophrenia. We examined its reliability and validity among outpatients with schizophrenia (N = 75) and mood disorders (N = 61). Because the hypothesized three-scale structure of the PANSS has not been supported by existing research, we also examined its factor structure. Interrater reliability for individual items and the positive and negative scales was demonstrated. Evidence supported the internal consistency of each scale in the overall sample and the schizophrenia group but was mixed among those with mood disorders. PANSS scores were higher in the schizophrenia group. These scores, in turn, were lower than those generally reported among inpatients with schizophrenia, providing known-groups validity evidence. Four of five factors were similar to those reported among inpatients with schizophrenia. Together, these results support the use of the PANSS among outpatients and reinforce existing support for assessing positive and negative symptoms in mood disorders.


Electrostatic environment of the tryptophylquinone cofactor in methylamine dehydrogenase: evidence from resonance Raman spectroscopy of model compounds.
Methylamine dehydrogenase (MADH) utilizes its endogenous tryptophan tryptophylquinone (TTQ) as a cofactor in enzymatic catalysis, with the C6 carbonyl of the quinone implicated as the site of attack by substrates and other nucleophiles. Resonance Raman (RR) spectroscopy provides an ideal method for investigating the state of this carbonyl group whose C==O stretch is distinct from other vibrational modes of the cofactor and is readily identified by its shift to lower energy in H218O. In a series of indole 6,7-quinone models for TTQ, the in-phase stretching vibration of the two C==O groups occurs at 1650 cm-1 in nonpolar solvents and shifts to 1638 cm-1 in H2O. The absorption maximum undergoes an analogous shift from 400 to 425 mm. The spectral properties of the indole quinones in H2O approach the corresponding values in Thiobacillus versutus MADH (C==O stretch at 1612 cm-1, lamdamax at 440mm) and are indicative of strongly hydrogen bonding of the C==O and NH groups of the cofactor in the native enzyme. Addition of monovalent cations [NH4+,Cs+, and (CH3)3NH+] to MADH causes further increases in the lamdamax and decreases in the frequency of the C==O stretch[1590 cm-1 with (CH3)3NH+]. This implies a strong electrostatic interaction between monovalent cations and a carbonyl oxygen (most likely at C6) in TTQ. The fact that these cations behave as competitive inhibitors of the methylamine substrate suggests that methylamine binds to the same location in the enzyme prior to its covalent reaction with the cofactor. Addition of monovalent cations to the one-electron-reduced semiquinone form MADH results in RR spectral shifts for a number of vibrational modes of the cofactor. Thus, the ability of monovalent cations to promote and stabilize the formation of the semiquinone intermediate is also due to their direct electrostatic interaction with the TTQ cofactor.


Recurrent tuberculosis and associated factors: A five - year countrywide study in Uzbekistan.
In Uzbekistan, despite stable and relatively high tuberculosis treatment success rates, relatively high rates of recurrent tuberculosis have recently been reported. Recurrent tuberculosis is when a patient who was treated for pulmonary tuberculosis and cured, later develops the disease again. This requires closer analysis to identify possible causes and recommend interventions to improve the situation. Using countrywide data, this study aimed to analyse trends in recurrent tuberculosis cases and describe their associations with socio-demographic and clinical factors. Countrywide retrospective cohort study comparing recurrent tuberculosis patients with all new tuberculosis patients registered within the NTP between January 2006 and December 2010 using routinely collected data. Determinants studied were baseline characteristics and treatment outcomes. Of 107,380 registered patients during the period January 2006 and December 2010, 9358 (8.7%) were recurrent cases. Between 2006 and 2008, the number of recurrent cases per annum increased from 1530 to 2081, then fell slightly thereafter from 2081 to 1888 cases. The proportion of all notified cases during this period increased from 6.5% to 9.9%. Factors associated with recurrent tuberculosis included age (35-55 years old), having smear positive pulmonary tuberculosis, residing in certain areas of Uzbekistan, having particular co-morbidities (including chronic obstructive pulmonary disease and HIV), and being unemployed, a pensioner or disabled. Recurrent tuberculosis patients also had a higher likelihood of having an unfavourable treatment outcome. Despite signs of declining national tuberculosis notifications between 2006 and 2010, the relative proportion of recurrent cases appears to have increased. These findings, together with the identification of possible risk factors associated with recurrent tuberculosis, highlight various areas where Uzbekistan needs to focus its tuberculosis control efforts, particularly in light of the country's rapidly emerging multi drug resistant tuberculosis epidemic.


Two-phase thermophilic anaerobic digestion process for biohythane production treating biowaste: preliminary results.
This paper deals with the optimization of a two-phase anaerobic process treating biowaste for hydrogen and methane production. Neither physical nor chemical pre-treatments were used to optimize the process. The work was carried out at pilot scale, using two CSTRs (200 and 380 L working volume respectively) both maintained at thermophilic temperature (55 C) and fed semi-continuously with biowaste. The experiment was divided into three periods; during the first two periods the organic loading rate was maintained at 20 kg TVS/m3 d and the hydraulic retention time was changed from 6.6 to 3.3 days, while in the last period the digestate of the second reactor was recirculated to the first reactor in order to buffer the system and control pH at levels around 5. The HRT was maintained at 3.3 days and the OLR was decreased at 16.5 kg TVS/m3 d. The best yield was obtained in the last period where a specific hydrogen production of 50.9 L/kg VSfed was reached, with a H2 content in biogas from the first reactor of 36%. The methanogenic stage after the hydrogen conversion reached a specific biogas production of 0.62 m3/kg VSfed and an overall organic removal above 70%, without any stability problem. The overall biogas production was some 1.5 m3 per day with a gas composition of 10% H2 and 50% CH4.


Occurrence and reassortment of avian influenza A (H7N9) viruses derived from coinfected birds in China.
Over the course of two waves of infection, H7N9 avian influenza A virus has caused 436 human infections and claimed 170 lives in China as of July 2014. To investigate the prevalence and genetic diversity of H7N9, we surveyed avian influenza viruses in poultry in Jiangsu province within the outbreak epicenter. We found frequent occurrence of H7N9/H9N2 coinfection in chickens. Molecular clock phylogenetic analysis confirms coinfection by H7N9/H9N2 viruses and also reveals that the identity of the H7N9 outbreak lineage is confounded by ongoing reassortment between outbreak viruses and diverse H9N2 viruses in domestic birds. Experimental inoculation of a coinfected sample in cell culture yielded two reassortant H7N9 strains with polymerase segments from the original H9N2 strain. Ongoing reassortment between the H7N9 outbreak lineage and diverse H9N2 viruses may generate new strains with the potential to infect humans, highlighting the need for continued viral surveillance in poultry and humans. We found frequent occurrence of H7N9/H9N2 coinfection in chickens. The H7N9 outbreak lineage is confounded by ongoing reassortment between H7N9 and H9N2 viruses. The importance of H9N2 viruses as the source of novel avian influenza virus infections in humans requires continuous attention.


Adaptive mutations of neuraminidase stalk truncation and deglycosylation confer enhanced pathogenicity of influenza A viruses.
It has been noticed that neuraminidase (NA) stalk truncation has arisen from evolutionary adaptation of avian influenza A viruses (IAVs) from wild aquatic birds to domestic poultry. We identified this molecular alteration after the adaptation of a 2009 pandemic H1N1 virus (pH1N1) in BALB/c mice. The mouse-adapted pH1N1 lost its eight consecutive amino acids including one potential N-linked glycosite from the NA stalk region. To explore the relationship of NA stalk truncation or deglycosylation with viral pathogenicity changes, we generated NA stalk mutant viruses on the pH1N1 backbone by reverse genetics. Intriguingly, either NA stalk truncation or deglycosylation changed pH1N1 into a lethal virus to mice by resulting in extensive pathologic transformation in the mouse lungs and systemic infection affecting beyond the respiratory organs in mice. The increased pathogenicity of these NA stalk mutants was also reproduced in ferrets. In further investigation using a human-infecting H7N9 avian IAV strain, NA stalk truncation or deglycosylation enhanced the replication property and pathogenicity of H7N9 NA stalk mutant viruses in the same mouse model. Taken together, our results suggest that NA stalk truncation or deglycosylation can be the pathogenic determinants of seasonal influenza viruses associated with the evolutionary adaptation of IAVs.


A systematic review on drugs absorption modifications after eradication in Helicobacter pylori positive patients undergoing replacement therapy.
Helicobacter pylori (H. pylori) infection has been suggested as a cause of impaired drug absorption. This infection leads to alteration of the gastric acid secretion that may change the conformational characteristics of drugs and their intestinal absorption leading to uncertainties about the dose to administer and the therapeutic results. A systematic review was undertaken to clarify the implications of drug absorption during the administration of replacement therapies. Electronic databases such as MEDLINE/Pubmed, EMBASE and The Cochrane Library [which includes Cochrane Database of Systematic Review (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstract of Reviews of Effect (DARE)] were searched. Grey literature databases (e.g. the International clinical trials registry platform, Trials Register, Clinical Trials.gov, Controlled Trials and TrialsCentral), Theses database, Government publication and LILACS database were also searched. No language restriction was applied. Infection and altered drug absorption were evaluated in patients under replacement therapies with iron, thyroxin and L-dopa. In all, seven studies included an improvement in drug absorption after eradication and an existing inverse correlation between the grade of gastric inflammation and indices of drug absorption were noticed. This systematic review confirmed the presence of an interaction between infection and drug absorption of orally administered replacement therapies. Gastric acid reduction and subsequent alteration of drug composition seem to lead this mechanism. Clinicians should be aware of this possible interaction when starting a replacement therapy in patients and when evaluating poor clinical response.


MO-A-217BCD-01: Internal Emitter Dose Estimation.
Tissue absorbed dose (D) is a computed result for internal emitters. For fixed geometries, D is calculated by a matrix (S) multiplication of the integrated activity vector (Ã). The last quantity is usually measured by nuclear imaging of activity in various source organs and performing a temporal integration. à is the same as the total number of source decays. Dose is computed for a number of target organs - some of which will be the same as the source organs. The D = S*à relationship is general in that the same formula may also be used for voxels within organs or even down to the cellular level. Finding the activity (A) in source tissues may be done by a number of methods of which 6 are described. The most common clinical technique is the geometric mean (GM) image of an organ. Uncertainties in the GM method are ≈ +/- 30%. If one can do quantitative SPECT, PET or CAMI imaging, the variation is reduced to around +/- 6%. These last three techniques, however, require fusion of anatomic (e.g. CT) and nuclear images. The S matrix is generated via Monte Carlo methods and may be used in two formats. The most common is a set of phantom-derived values for regulatory or scientific considerations. An example is the OLINDA program from Vanderbilt University. In this case, the corresponding animal or patient à value must be normalized using blood flow arguments. A second format is modification of a phantom's S values for a particular patient using the latter's geometry as found in CT or MRI scans. Corrections in such cases may be 2-fold or more because of patient organ size variability. These variations may be due to genetic reasons and/or disease. Two caveats to the use of the above dose formulation should be mentioned. One exception is that the geometry may vary during tissue irradiation; e.g., by tumor size decrease due to immediate radiation dose effects. In this case, the standard formula is replaced by its differential form: dD/dt = S(t)*A(t). Dose rate may also be an important biological factor in assessing tissue response. A second important biological consideration is that effects - such as tumor regression - may depend upon higher powers of D than the first. Thus, the tissue response may not be a linear function of D, but would exhibit a sigmoid shape. One would anticipate such responses due to saturation of a biological system. 1. Knowing the general formula for internal emitter absorbed dose estimation. 2. Understanding the various methods used to measure activity, at depth, in source organs in a living animal or patient. 3. Realizing that two types of dose may be computed: one for a phantom and a second type for an individual patient. S values must be modified accordingly for these two computations. 4. Estimating uncertainties - including those in both à and S - involved in the dose estimation process.


Evaluating frailty, mortality, and complications associated with metastatic spine tumor surgery using machine learning-derived body composition analysis.
Cancer patients with spinal metastases may undergo surgery without clear assessments of prognosis, thereby impacting the optimal palliative strategy. Because the morbidity of surgery may adversely impact recovery and initiation of adjuvant therapies, evaluation of risk factors associated with mortality risk and complications is critical. Evaluation of body composition of cancer patients as a surrogate for frailty is an emerging area of study for improving preoperative risk stratification. To examine the associations of muscle characteristics and adiposity with postoperative complications, length of stay, and mortality in patients with spinal metastases, the authors designed an observational study of 484 cancer patients who received surgical treatment for spinal metastases between 2010 and 2019. Sarcopenia, muscle radiodensity, visceral adiposity, and subcutaneous adiposity were assessed on routinely available 3-month preoperative CT images by using a validated deep learning methodology. The authors used k-means clustering analysis to identify patients with similar body composition characteristics. Regression models were used to examine the associations of sarcopenia, frailty, and clusters with the outcomes of interest. Of 484 patients enrolled, 303 had evaluable CT data on muscle and adiposity (mean age 62.00 ± 11.91 years; 57.8% male). The authors identified 2 clusters with significantly different body composition characteristics and mortality risks after spine metastases surgery. Patients in cluster 2 (high-risk cluster) had lower muscle mass index (mean ± SD 41.16 ± 7.99 vs 50.13 ± 10.45 cm2/m2), lower subcutaneous fat area (147.62 ± 57.80 vs 289.83 ± 109.31 cm2), lower visceral fat area (82.28 ± 48.96 vs 239.26 ± 98.40 cm2), higher muscle radiodensity (35.67 ± 9.94 vs 31.13 ± 9.07 Hounsfield units [HU]), and significantly higher risk of 1-year mortality (adjusted HR 1.45, 95% CI 1.05-2.01, p = 0.02) than individuals in cluster 1 (low-risk cluster). Decreased muscle mass, muscle radiodensity, and adiposity were not associated with a higher rate of complications after surgery. Prolonged length of stay (> 7 days) was associated with low muscle radiodensity (mean 30.87 vs 35.23 HU, 95% CI 1.98-6.73, p < 0.001). Body composition analysis shows promise for better risk stratification of patients with spinal metastases under consideration for surgery. Those with lower muscle mass and subcutaneous and visceral adiposity are at greater risk for inferior outcomes.


Genomic diversity of Escherichia coli isolates from non-human primates in the Gambia.
Increasing contact between humans and non-human primates provides an opportunity for the transfer of potential pathogens or antimicrobial resistance between host species. We have investigated genomic diversity and antimicrobial resistance in Escherichia coli isolates from four species of non-human primates in the Gambia: Papio papio (n=22), Chlorocebus sabaeus (n=14), Piliocolobus badius (n=6) and Erythrocebus patas (n=1). We performed Illumina whole-genome sequencing on 101 isolates from 43 stools, followed by nanopore long-read sequencing on 11 isolates. We identified 43 sequence types (STs) by the Achtman scheme (ten of which are novel), spanning five of the eight known phylogroups of E. coli. The majority of simian isolates belong to phylogroup B2 - characterized by strains that cause human extraintestinal infections - and encode factors associated with extraintestinal disease. A subset of the B2 strains (ST73, ST681 and ST127) carry the pks genomic island, which encodes colibactin, a genotoxin associated with colorectal cancer. We found little antimicrobial resistance and only one example of multi-drug resistance among the simian isolates. Hierarchical clustering showed that simian isolates from ST442 and ST349 are closely related to isolates recovered from human clinical cases (differences in 50 and 7 alleles, respectively), suggesting recent exchange between the two host species. Conversely, simian isolates from ST73, ST681 and ST127 were distinct from human isolates, while five simian isolates belong to unique core-genome ST complexes - indicating novel diversity specific to the primate niche. Our results are of planetary health importance, considering the increasing contact between humans and wild non-human primates.


Validation of targeted microsurgical spermatic cord denervation: comparison of outcomes to traditional complete microsurgical spermatic cord denervation.
The aim of this study was to validate the effectiveness of targeted microsurgical spermatic cord denervation (MSCD) of the trifecta nerve complex in comparison to traditional full MSCD with complete skeletonization of the spermatic cord in men with chronic orchialgia. Retrospective chart review was performed by a single fellowship-trained microsurgeon between 2011 and 2016. Patients had follow-ups at 6 weeks, 6 months, and 1 year postoperatively. Thirty-nine men with chronic orchialgia underwent full MSCD between 2011 and 2013. In July 2013, after the publication of an anatomic study with identification of Wallerian degeneration of the trifecta nerve complex in men with chronic orchialgia, the technique was changed to targeted MSCD. From July 2013 to March 2016, 43 men underwent targeted MSCD. When comparing the full MSCD group to the targeted MSCD group, there was no significant difference in resolution of pain (66.7% vs 69.8%, P = 0.88), no difference in partial relief of pain (17.9% vs 23.3%, P = 0.55), and no difference in failure to respond rates (15.4% vs 7.0%, P = 0.22) between the two groups. There was no difference in mean change of visual analog pain scale scores between the two groups (P = 0.27). Targeted MSCD had a shorter operative time (53 min vs 21 min, P = 0.0001). Targeted MSCD offers patients comparable outcomes to traditional full MSCD, with a shorter operative time, a less technically challenging surgery, and potentially less risk to cord structures which should be preserved.


Effect of increased preload on the synthesized aortic blood pressure waveform.
In the present study, we examined the influence of preload augmentation via passive leg elevation (PLE) on synthesized aortic blood pressure, aortic augmentation index (AIx), and aortic capacitance (a reflection of aortic reservoir function). Central and peripheral hemodynamics were measured via tonometry with a generalized transfer function in 14 young, healthy men (age = 24 yr). Aortic blood flow was calculated from the left ventricular outflow tract (LVOT) velocity-time integral (VTI) using standard two-dimensional echocardiographic-Doppler techniques. Measures were made in the supine position at rest (Pre), during PLE, and during recovery (Post). There was a significant increase in LVOT-VTI, synthesized aortic systolic blood pressure (BP) and AIx from Pre to PLE, with values returning to baseline Post (P < 0.05). There was a reduction in aortic capacitance from Pre to PLE, with values returning to baseline Post (P < 0.05). There was no change in heart rate, systemic arterial compliance, aortic elastance, aortic wave travel timing, or vascular resistance (P > 0.05). Change in AIx from Pre to PLE was associated with change in LVOT-VTI (r = 0.66, P < 0.05) and inversely associated with change in aortic capacitance (r = -0.73, P < 0.05). These data suggest that in a setting of isolated augmented preload with minimal changes in other potential confounders, the morphology of the synthesized aortic BP waveform and AIx may be related to changes in aortic reservoir function.


Complete Genome Sequence of a Legionella longbeachae Serogroup 1 Strain Isolated from a Patient with Legionnaires' Disease.
Legionella longbeachae serogroup 1, predominantly found in soil and composted plant material, causes the majority of cases of Legionnaires' disease (LD) in New Zealand. Here, we report the complete genome sequence of an L. longbeachae serogroup 1 (sg1) isolate derived from a patient hospitalized with LD in Christchurch, New Zealand.


Elevated endothelial-cell-stimulating angiogenic factor activity in rodent glycolytic skeletal muscles.
1. Capillary density is greater in skeletal muscles comprised of predominantly oxidative (type I) fibres than in those comprised of mainly glycolytic (type II) fibres. In order to investigate further the angiogenic mechanisms involved in muscle capillarization, endothelial-cell-stimulating angiogenic factor activities in various rodent skeletal muscles were compared. 2. Eleven untrained adult male Wistar rats were killed and the predominantly oxidative (type I) muscle,s soleus and heart, the predominantly glycolytic (type II) muscle, extensor digitorum longus, and the mixed-fibre muscle, gastrocnemius, were removed. Each sample was separately homogenized and centrifuged and the supernatants were diafiltered to isolate the low-molecular-mass fraction containing endothelial-cell-stimulating angiogenic activity. This was assayed for its ability to activate latent collagenase and was expressed as units, where 1 unit represents the percentage activation of the enzyme h-1 (mg of protein in the supernatant)-1. 3. The results (medians and ranges) demonstrated significantly greater endothelial-cell-stimulating angiogenic factor activity in extensor digitorum longus muscle (2.14 units, 0.62-2.87 units, n = 13) than in soleus (0.82 units, 0.59-1.79 units, n = 15), gastrocnemius (0.34 units, 0.28-0.40 units, n = 4) or heart (0.43 units, 0.16-0.52 units, n = 11) (P less than 0.01 for each) muscle. 4. These findings suggest that endothelial-cell-stimulating angiogenic activity in muscle is either inversely or not related to the local capillary density, which may be at or near a maximum in physiologically contracting, predominantly oxidative muscles.


Stigma, disclosure, coping, and medication adherence among people living with HIV/AIDS in Northern Tanzania.
This study examines a proposed theoretical model examining the interrelationships between stigma, disclosure, coping, and medication adherence among 158 HIV-infected patients on antiretroviral therapy (ART) in northern Tanzania. Perceived and self-stigma, voluntary and involuntary disclosure, positive and negative coping, and demographics were assessed by trained interviewers, and self-reported adherence was collected during 5 months follow-up. Data were examined using correlation and regression analyses. The analyses showed that perceived stigma is primarily related to involuntary disclosure, whereas self-stigma is related to voluntary disclosure. Religious coping positively relates to acceptance, whereas perceived stigma explains higher levels of denial of HIV status. Lastly, adherence was negatively affected by alcohol use, self-stigma, and denial. We conclude that adherence is predominantly predicted by negative rather than positive coping mechanisms. Therefore, substituting maladaptive coping mechanisms like denial and alcohol use with a more adaptive coping style may be an important strategy to improve long-term ART adherence and well-being of patients. Moreover, this study showed that it is useful to examine both involuntary and voluntary disclosure when studying its relation with stigma.


Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US medicaid population with HIV.
Lower pill burden leads to improved antiretroviral therapy (ART) adherence among HIV patients. Simpler dosing regimens have not been widely explored in real-world populations. We retrospectively assessed ART adherence, all-cause hospitalisation risk and costs, and other healthcare utilisation and costs in Medicaid enrollees with HIV treated with ART as a once-daily single-tablet regimen (STR) or two or more pills per day (2+PPD). Patients with an HIV diagnosis from 2005 to 2009 receiving complete ART (ie, two nucleoside/nucleotide reverse transcriptase inhibitors plus a third agent) for ≥60 days as STR or 2+PPD were selected and followed until the first of (1) discontinuation of the complete ART, (2) loss of enrolment or (3) end of database. Adherence was measured using the medication possession ratio. Monthly all-cause healthcare utilisation and costs were observed from regimen initiation until follow-up end. Of the 7381 patients who met inclusion criteria, 1797 were treated with STR and 5584 with 2+PPD. STR patients were significantly more likely to reach 95% adherence and had fewer hospitalisations than 2+PPD patients (both p<0.01). STR patients had mean (SD) total monthly costs of $2959 ($4962); 2+PPD patients had $3544 ($5811; p<0.001). Hospital costs accounted for 53.8% and pharmacy costs accounted for 32.5% of this difference. Multivariate analyses found that STR led to a 23% reduction in hospitalisations and a 17% reduction in overall healthcare costs. ART adherence appears to be a key mechanism mediating hospitalisation risk, as patients with ≥95% adherence (regardless of regimen type) had a lower hospitalisation rate compared with <95% adherence. While it was expected that STR patients would have lower pharmacy costs, we also found that STR patients had fewer hospitalisations and lower hospital costs than 2+PPD patients, resulting in significantly lower total healthcare costs for STR patients.


Economic poverty among children and adolescents in the Nordic countries.
This study aimed to identify applied definitions and measurements of economic poverty and to explore the proportions and characteristics of children and adolescents living in economic poverty in Denmark, Finland, Iceland, Norway and Sweden during the last decade and to compare various statistics between the Nordic countries. Official data from central national authorities on statistics, national reports and European Union Statistics of income and living conditions data were collected and analysed during 2015-2016. The proportion of Nordic children living in economic poverty in 2014 ranged from 9.4% in Norway to 18.5% in Sweden. Compared with the European Union average, from 2004 to 2014 Nordic families with dependent children experienced fewer difficulties in making their money last, even though Icelandic families reported considerable difficulties. The characteristics of children living in economic poverty proved to be similar in the five countries and were related to their parents' level of education and employment, single-parent households and - in Denmark, Norway and Sweden - to immigrant background. In Finland, poverty among children was linked in particular to low income in employed households. This study showed that economic poverty among Nordic families with dependent children has increased during the latest decade, but it also showed that poverty rates are not necessarily connected to families' ability to make their money last. Therefore additional studies are needed to explore existing policies and political commitments in the Nordic countries to compensate families with dependent children living in poverty.


MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development.
miRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here, we report evidence implicating the miR100 in self-renewal of cancer stem-like cells (CSC). We found that miR100 expression levels relate to the cellular differentiation state, with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR100 in human cells, we found that increasing miR100 levels decreased the production of breast CSCs. This effect was correlated with an inhibition of cancer cell proliferation in vitro and in mouse tumor xenografts due to attenuated expression of the CSC regulatory genes SMARCA5, SMARCD1, and BMPR2. Furthermore, miR100 induction in breast CSCs immediately upon their orthotopic implantation or intracardiac injection completely blocked tumor growth and metastasis formation. Clinically, we observed a significant association between miR100 expression in breast cancer specimens and patient survival. Our results suggest that miR100 is required to direct CSC self-renewal and differentiation.


Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial.
Pleurodesis is done as an in-patient procedure to control symptomatic recurrent malignant pleural effusion (MPE) and has a success rate of 75-80%. Thoracic ultrasonography has been shown in a small study to predict pleurodesis success early by demonstrating cessation of lung sliding (a normal sign seen in healthy patients, lung sliding indicates normal movement of the lung inside the thorax). We aimed to investigate whether the use of thoracic ultrasonography in pleurodesis pathways could shorten hospital stay in patients with MPE undergoing pleurodesis. The Efficacy of Sonographic and Biological Pleurodesis Indicators of Malignant Pleural Effusion (SIMPLE) trial was an open-label, randomised controlled trial done in ten respiratory centres in the UK and one respiratory centre in the Netherlands. Adult patients (aged ≥18 years) with confirmed MPE who required talc pleurodesis via either a chest tube or as poudrage during medical thorascopy were eligible. Patients were randomly assigned (1:1) to thoracic ultrasonography-guided care or standard care via an online platform using a minimisation algorithm. In the intervention group, daily thoracic ultrasonography examination for lung sliding in nine regions was done to derive an adherence score: present (1 point), questionable (2 points), or absent (3 points), with a lowest possible score of 9 (preserved sliding) and a highest possible score of 27 (complete absence of sliding); the chest tube was removed if the score was more than 20. In the standard care group, tube removal was based on daily output volume (per British Thoracic Society Guidelines). The primary outcome was length of hospital stay, and secondary outcomes were pleurodesis failure at 3 months, time to tube removal, all-cause mortality, symptoms and quality-of-life scores, and cost-effectiveness of thoracic ultrasonography-guided care. All outcomes were assessed in the modified intention-to-treat population (patients with missing data excluded), and a non-inferiority analysis of pleurodesis failure was done in the per-protocol population. This trial was registered with ISRCTN, ISRCTN16441661. Between Dec 31, 2015, and Dec 17, 2019, 778 patients were assessed for eligibility and 313 participants (165 [53%] male) were recruited and randomly assigned to thoracic ultrasonography-guided care (n=159) or standard care (n=154). In the modified intention-to-treat population, the median length of hospital stay was significantly shorter in the intervention group (2 days [IQR 2-4]) than in the standard care group (3 days [2-5]; difference 1 day [95% CI 1-1]; p<0·0001). In the per-protocol analysis, thoracic ultrasonography-guided care was non-inferior to standard care in terms of pleurodesis failure at 3 months, which occurred in 27 (29·7%) of 91 patients in the intervention group versus 34 (31·2%) of 109 patients in the standard care group (risk difference -1·5% [95% CI -10·2% to 7·2%]; non-inferiority margin 15%). Mean time to chest tube removal in the intervention group was 2·4 days (SD 2·5) versus 3·1 days (2·0) in the standard care group (mean difference -0·72 days [95% CI -1·22 to -0·21]; p=0·0057). There were no significant between-group differences in all-cause mortality, symptom scores, or quality-of-life scores, except on the EQ-5D visual analogue scale, which was significantly lower in the standard care group at 3 months. Although costs were similar between the groups, thoracic ultrasonography-guided care was cost-effective compared with standard care. Thoracic ultrasonography-guided care for pleurodesis in patients with MPE results in shorter hospital stay (compared with the British Thoracic Society recommendation for pleurodesis) without reducing the success rate of the procedure at 3 months. The data support consideration of standard use of thoracic ultrasonography in patients undergoing MPE-related pleurodesis. Marie Curie Cancer Care Committee.


Health care development: integrating transaction cost theory with social support theory.
The emergence of Web 2.0 technologies has already been influential in many industries, and Web 2.0 applications are now beginning to have an impact on health care. These new technologies offer a promising approach for shaping the future of modern health care, with the potential for opening up new opportunities for the health care industry as it struggles to deal with challenges including the need to cut costs, the increasing demand for health services and the increasing cost of medical technology. Social media such as social networking sites are attracting more individuals to online health communities, contributing to an increase in the productivity of modern health care and reducing transaction costs. This study therefore examines the potential effect of social technologies, particularly social media, on health care development by adopting a social support/transaction cost perspective. Viewed through the lens of Information Systems, social support and transaction cost theories indicate that social media, particularly online health communities, positively support health care development. The results show that individuals join online health communities to share and receive social support, and these social interactions provide both informational and emotional support.


Side-stream smoking reduces intestinal inflammation and increases expression of tight junction proteins.
To investigate the effect of side-stream smoking on gut microflora composition, intestinal inflammation and expression of tight junction proteins. C57BL/6 mice were exposed to side-stream cigarette smoking for one hour daily over eight weeks. Cecal contents were collected for microbial composition analysis. Large intestine was collected for immunoblotting and quantitative reverse transcriptase polymerase chain reaction analyses of the inflammatory pathway and tight junction proteins. Side-stream smoking induced significant changes in the gut microbiota with increased mouse intestinal bacteria, Clostridium but decreased Fermicutes (Lactoccoci and Ruminococcus), Enterobacteriaceae family and Segmented filamentous baceteria compared to the control mice. Meanwhile, side-stream smoking inhibited the nuclear factor-κB pathway with reduced phosphorylation of p65 and IκBα, accompanied with unchanged mRNA expression of tumor necrosis factor-α or interleukin-6. The contents of tight junction proteins, claudin3 and ZO2 were up-regulated in the large intestine of mice exposed side-stream smoking. In addition, side-stream smoking increased c-Jun N-terminal kinase and p38 MAPK kinase signaling, while inhibiting AMP-activated protein kinase in the large intestine. Side-stream smoking altered gut microflora composition and reduced the inflammatory response, which was associated with increased expression of tight junction proteins.


Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures.
Friedreich's ataxia (FRDA) is a rare autosomal-recessive slowly progressive neurodegenerative disorder. As common clinical measures for this devastating disease lack sensitivity, we explored whether (a) the quantitative motor assessments of the Q-Motor battery can enhance clinical characterisation of FRDA; (b) clinical measures can predict Q-Motor outcomes and (c) Q-Motor is sensitive to longitudinal change. At baseline 29 patients and 23 controls and in a 1-year follow-up 14 patients and 6 controls were included. The Q-Motor included lift (manumotography), finger tapping (digitomotography) and pronate/supinate (dysdiadochomotography) tasks. To model responses, a search of generalised linear models was conducted, selecting best fitting models, using demographic and clinical data as predictors. Predictors from selected models were used in linear mixed models to investigate longitudinal changes. Patients with FRDA performed worse than controls on most measures. Modelling of the pronate/supinate task was dominated by SCAFI (SCA functional index) subtasks, while tapping task and lift task models suggested a complex relationship with clinical measures. Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients. Further longitudinal research is warranted to fully characterise its relation to routinely used measures and scales for FRDA.


Diffusion weighted and dynamic contrast enhanced MRI as an imaging biomarker for stereotactic ablative body radiotherapy (SABR) of primary renal cell carcinoma.
To explore the utility of diffusion and perfusion changes in primary renal cell carcinoma (RCC) after stereotactic ablative body radiotherapy (SABR) as an early biomarker of treatment response, using diffusion weighted (DWI) and dynamic contrast enhanced (DCE) MRI. Patients enrolled in a prospective pilot clinical trial received SABR for primary RCC, and had DWI and DCE MRI scheduled at baseline, 14 days and 70 days after SABR. Tumours <5cm diameter received a single fraction of 26 Gy and larger tumours received three fractions of 14 Gy. Apparent diffusion coefficient (ADC) maps were computed from DWI data and parametric and pharmacokinetic maps were fitted to the DCE data. Tumour volumes were contoured and statistics extracted. Spearman's rank correlation coefficients were computed between MRI parameter changes versus the percentage tumour volume change from CT at 6, 12 and 24 months and the last follow-up relative to baseline CT. Twelve patients were eligible for DWI analysis, and a subset of ten patients for DCE MRI analysis. DCE MRI from the second follow-up MRI scan showed correlations between the change in percentage voxels with washout contrast enhancement behaviour and the change in tumour volume (ρ = 0.84, p = 0.004 at 12 month CT, ρ = 0.81, p = 0.02 at 24 month CT, and ρ = 0.89, p = 0.001 at last follow-up CT). The change in mean initial rate of enhancement and mean Ktrans at the second follow-up MRI scan were positively correlated with percent tumour volume change at the 12 month CT onwards (ρ = 0.65, p = 0.05 and ρ = 0.66, p = 0.04 at 12 month CT respectively). Changes in ADC kurtosis from histogram analysis at the first follow-up MRI scan also showed positive correlations with the percentage tumour volume change (ρ = 0.66, p = 0.02 at 12 month CT, ρ = 0.69, p = 0.02 at last follow-up CT), but these results are possibly confounded by inflammation. DWI and DCE MRI parameters show potential as early response biomarkers after SABR for primary RCC. Further prospective validation using larger patient cohorts is warranted.


Correlations of genotype and phenotype in hypophosphatasia.
Hypophosphatasia, a rare inherited disorder characterized by defective bone mineralization, is highly variable in its clinical expression. The disease is due to various mutations in the tissue-non-specific alkaline phosphatase ( TNSALP ) gene. We report here the use of clinical data, site-directed mutagenesis and computer-assisted modelling to propose a classification of 32 TNSALP gene mutations found in 23 European patients, 17 affected with lethal hypophosphatasia and six with non-lethal hypophosphatasia. Transfection studies of the missense mutations found in non-lethal hypophosphatasia showed that six of them allowed significant residual in vitro enzymatic activity, suggesting that these mutations corresponded to moderate alleles. Each of the six patients with non-lethal hypophosphatasia carried at least one of these alleles. The three-dimensional model study showed that moderate mutations were not found in the active site, and that most of the severe missense mutations were localized in crucial domains such as the active site, the vicinity of the active site and homodimer interface. Some mutations appeared to be organized in clusters on the surface of the molecule that may represent possible candidates for regions interacting with the C-terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with other dimers to form tetramers. Finally, our results show a good correlation between clinical forms of the disease, mutagenesis experiments and the three-dimensional structure study, and allowed us to clearly distinguish moderate alleles from severe alleles. They also confirm that the extremely high phenotypic heterogeneity observed in patients with hypophosphatasia was due mainly to variable residual enzymatic activities allowed by missense mutations found in the human TNSALP gene.


DegePrime, a program for degenerate primer design for broad-taxonomic-range PCR in microbial ecology studies.
The taxonomic composition of a microbial community can be deduced by analyzing its rRNA gene content by, e.g., high-throughput DNA sequencing or DNA chips. Such methods typically are based on PCR amplification of rRNA gene sequences using broad-taxonomic-range PCR primers. In these analyses, the use of optimal primers is crucial for achieving an unbiased representation of community composition. Here, we present the computer program DegePrime that, for each position of a multiple sequence alignment, finds a degenerate oligomer of as high coverage as possible and outputs its coverage among taxonomic divisions. We show that our novel heuristic, which we call weighted randomized combination, performs better than previously described algorithms for solving the maximum coverage degenerate primer design problem. We previously used DegePrime to design a broad-taxonomic-range primer pair that targets the bacterial V3-V4 region (341F-805R) (D. P. Herlemann, M. Labrenz, K. Jurgens, S. Bertilsson, J. J. Waniek, and A. F. Andersson, ISME J. 5:1571-1579, 2011, http://dx.doi.org/10.1038/ismej.2011.41), and here we use the program to significantly increase the coverage of a primer pair (515F-806R) widely used for Illumina-based surveys of bacterial and archaeal diversity. By comparison with shotgun metagenomics, we show that the primers give an accurate representation of microbial diversity in natural samples.


Improving the efficacy of cancer immunotherapy.
A series of cancer vaccines have been evaluated in clinical trials with encouraging results, but the demonstration of clinical benefit in confirmatory studies has so far proven to be difficult. The development of cancer vaccines is hampered by a range of issues particular to this field of research. On 12th March 2008, the Biotherapy Development Association convened a workshop to discuss issues faced by scientists and clinicians involved in the development of cancer vaccines. This paper is a review of the field, based on discussions held at the BDA workshop, and describes biological barriers encountered in generating effective immune responses to tumours, methodological obstacles encountered in the improvement of immunological monitoring which aims to improve inter-laboratory and inter-trial comparisons, challenges in clinical trial design and problems posed by the lack of specific regulation for cancer vaccines and the impact on their development. Ultimately, a number of general solutions are posed: (1) better patient selection, (2) use of multi-modal treatments that affect several aspects of the immune system at once, (3) a requirement for the development of good biomarkers to stratify patients for selection prior to trial and as surrogates for clinical response and (4) harmonisation of SOPs for immunological monitoring of clinical trials.


Why are the Pakistani maternal, fetal and newborn outcomes so poor compared to other low and middle-income countries?
Pakistan has among the poorest pregnancy outcomes worldwide, significantly worse than many other low-resource countries. The reasons for these differences are not clear. In this study, we compared pregnancy outcomes in Pakistan to other low-resource countries and explored factors that might help explain these differences. The Global Network (GN) Maternal Newborn Health Registry (MNHR) is a prospective, population-based observational study that includes all pregnant women and their pregnancy outcomes in defined geographic communities in six low-middle income countries (India, Pakistan, Democratic Republic of Congo, Guatemala, Kenya, Zambia). Study staff enroll women in early pregnancy and follow-up soon after delivery and at 42 days to ascertain delivery, neonatal, and maternal outcomes. We analyzed the maternal mortality ratios (MMR), neonatal mortality rates (NMR), stillbirth rates, and potential explanatory factors from 2010 to 2018 across the GN sites. From 2010 to 2018, there were 91,076 births in Pakistan and 456,276 births in the other GN sites combined. The MMR in Pakistan was 319 per 100,000 live births compared to an average of 124 in the other sites, while the Pakistan NMR was 49.4 per 1,000 live births compared to 20.4 in the other sites. The stillbirth rate in Pakistan was 53.5 per 1000 births compared to 23.2 for the other sites. Preterm birth and low birthweight rates were also substantially higher than the other sites combined. Within weight ranges, the Pakistani site generally had significantly higher rates of stillbirth and neonatal mortality than the other sites combined, with differences increasing as birthweights increased. By nearly every measure, medical care for pregnant women and their newborns in the Pakistan sites was worse than at the other sites combined. The Pakistani pregnancy outcomes are much worse than those in the other GN sites. Reasons for these poorer outcomes likely include that the Pakistani sites' reproductive-aged women are largely poorly educated, undernourished, anemic, and deliver a high percentage of preterm and low-birthweight babies in settings of often inadequate maternal and newborn care. By addressing the issues highlighted in this paper there appears to be substantial room for improvements in Pakistan's pregnancy outcomes.


The importance of A9 dopaminergic neurons in mediating the functional benefits of fetal ventral mesencephalon transplants and levodopa-induced dyskinesias.
Intrastriatal transplantation of fetal ventral mesencephalon (VM) tissue provides the potential to alleviate motor symptoms of Parkinson's disease (PD) and levodopa-induced dyskinesia (LID). However, the degree of recovery varies among individuals with an incidence of "off-phase", graft-induced dyskinesia (GID) in some patients. We hypothesised that this variability is due to the heterogeneous nature of dopaminergic neurons in the transplant. We therefore investigated this in the unilateral 6-hydroxydopamine-lesioned rat model of PD. These animals were primed to develop LID and then transplanted with fetal VM into the caudal aspects of the striatum. No GID was observed but in a significant number of animals the transplants ameliorated LID. There was a correlation between the degree of behavioural and LID recovery with the number of A9 dopaminergic neurons in the transplant, based on their expression of a G-protein-coupled inward rectifying current potassium channel (Girk2). Furthermore, we showed that LID development is related to an abnormal expression profile of cyclin-dependent kinase 5 (Cdk5) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the striatum and that intrastriatal VM transplants normalised both Cdk5 expression and DARPP-32 phosphorylation in animals exhibiting functional improvement. These results suggest that an A9 dopaminergic neuron-enriched transplant may be the key to an effective PD cell replacement therapy through normalisation of the altered striatal expression of Cdk5/DARPP-32.


Black West Indian and matched white diabetics in Britain compared with diabetics in Jamaica: body mass, blood pressure, and vascular disease.
This study was designed to compare the prevalence of obesity, high blood pressure, diabetic vascular disease, and risk factors in Black West Indians who had emigrated to Britain (WIB) with those in Whites in England and among diabetic Jamaicans in Jamaica. Seventy-seven consecutive WIB patients were matched for age, sex, known duration of diabetes, and type of treatment of diabetes with 74 Whites from the same diabetes clinic in England. In Jamaica, a systematic random sample (95 women, 36 men) was studied. There was no difference in age at diagnosis between WIBs and Jamaicans. Effort chest pain (possible angina) was less frequent in WIBs (9%) or Jamaicans (3%) than in Whites (25%). Cigarette smoking was more common in WIBs than in Whites but still low in Jamaicans. Body mass index was greatest in WIB women (85%), significantly more than in matched White (52%) or Jamaican women (45%); 40% of White men and WIB men were obese, significantly more than Jamaicans (15% obese). Systolic blood pressure was similar, but diastolic blood pressure was significantly greater in WIBs than in matched White subjects. The prevalence of casual hypertension was high (greater than 40%) in all groups, often despite treatment. Cataracts were significantly more frequent in WIB and Jamaican groups than in Whites. Total background retinopathy after correcting for duration of diabetes did not differ between groups, and there were no significant differences in other complication rates. Levels of HbA1 were lower in Whites than in the other groups. Regression analysis showed that systolic blood pressure was most consistently related to complications, particularly retinopathy, independent of ethnic group and duration.(ABSTRACT TRUNCATED AT 250 WORDS)


Stuttering Following Acquired Brain Damage: A Review of the Literature.
Communication problems resulting from acquired brain damage are most frequently manifested as motor speech disorders such as dysarthria, syndromes of aphasia, and impairments of pragmatics. A much less common phenomenon is the onset of stuttering in adults who sustain a stroke, traumatic brain injury, or other neurologic events. When stuttering occurs in association with neuropathology, precise characterization and explanation of observed behaviors is often difficult. Among the clinical challenges presented by acquired stuttering are the problem of distinguishing this form of dysfluency from those associated with dysarthria and aphasia, and identifying the neuropathological condition(s) and brain lesion site(s) giving rise to this speech disorder. Another challenge to the precise characterization of acquired stuttering is the fact that some cases of acquired stuttering apparently have a psychological or neuropsychiatric genesis rather than a neuropathological one. In this paper we provide a review of the literature pertaining to the complicated phenomenon of acquired stuttering in adults and draw some tentative explanatory conclusions regarding this disorder.


Associations between executive function and physical function poststroke: a pilot study.
Associations between executive function and physical function poststroke have not been extensively studied. More complex physiotherapy interventions poststroke require a greater degree of cognitive ability, especially executive function. This pilot study aimed to inform the methodology of a larger study by examining the associations between executive function and the performance of basic and complex gait tasks in people poststroke. A cross-sectional pilot study was conducted in a convenience sample of 20 participants recruited from a community-based voluntary stroke organisation and from the outpatient services of two urban hospitals. A battery of tests was used to measure executive function (Trail Making Test, Stroop Word-Colour Test, Zoo Map test, Frontal Assessment Battery and Digit Span backward test). Basic and complex 10metre gait tests were used to mimic aspects of physiotherapy intervention poststroke. Other measures included the Mini-Mental State Examination (MMSE) and the Motor Assessment Scale (MAS). Observational comparisons between participant executive function scores and age- and/or education-matched normative data demonstrated that executive dysfunction ranged between 55% and 100%. Poorer performance in measures of executive function was more frequently associated with poorer performance in complex gait tests compared with basic gait tests. The MAS was not significantly associated with any measure of executive function. Executive dysfunction is a common sequel poststroke which may negatively affect physical performance. Physiotherapists should consider executive dysfunction when developing rehabilitation strategies to improve physical function poststroke.


An evaluation of the maintenance to abstinence (MTA) program in achieving abstinence in opioid users and improving mental health and quality of life.
Residential opioid rehabilitation aims to improve the mental health and quality of life of opioid users through abstinence and residential program participation. This study aimed to determine the depression, anxiety, stress and quality of life amongst maintenance to abstinence (MTA) program residents. Secondary study aims were to assess the personal characteristics of MTA clients, addiction and risk taking behaviours, factors associated with program completion, as well as to assess the reliable change in participants' mental health and quality of life on exit. Retrospective analysis of routinely collected data (2013-2017) from surveys completed by 100 clients. Outcome measures were: Depression, Anxiety, Stress Score (DASS-42), World Health Organisation Quality of Life 8 questions (WHOQOL-8) and Kessler Psychological Distress Scale (K10). Other variables included demographics, drug use, other addictions, aggression, self-harm, suicidal ideation/attempts, and risk taking behaviours. Statistical methods included Chi-square, Fisher's exact, t-tests, repeated measures analysis of variance and the Reliable Change Index. All mean DASS-42, WHOQOL-8 and K10 scores improved significantly in all participants from entry to exit (p < 0.001). The majority of participants demonstrated reliable improvement across all psychometric measures. Completion rates for the MTA program were 51%. Depression (p = 0.023), anxiety (p = 0.010) and stress (p = 0.015) DASS-42 scores decreased significantly more in completers compared to non-completers. The rate of improvement in mean WHOQOL-8 scores and psychological distress scores (K10) was not statistically significantly different between completers and non-completers over time. There was no significant difference between completers and non-completers on socio-demographics, self-reported drug addiction or risk taking behaviour on program entry, except for suicidal thoughts while intoxicated (p = 0.033). Completers were more satisfied with their relationships (p = 0.044) and living place (p = 0.040) on program entry. Overall, completers and non-completers demonstrated improved mental health and quality of life from entry to exit, regardless of program completion. Depression, anxiety and stress reduced more markedly in program completers. Policy makers and programmers could use these findings to further validate their own programs to improve mental health and quality of life of opioid users.


Antitumor effects of a combined 5-aza-2'deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice.
Patched (Ptch) heterozygous mice develop medulloblastoma (MB) and rhabdomyosarcoma (RMS) resembling the corresponding human tumors. We have previously shown that epigenetic silencing of the intact Ptch allele contributes to tumor formation in this model. Here, we investigated whether targeting of epigenetic silencing mechanisms could be useful in the treatment of Ptch-associated cancers. A reduction of endogenous DNA methyltransferase1 (Dnmt1) activity significantly reduced tumor incidence in heterozygous Ptch knockout mice. A combined treatment with the Dnmt inhibitor 5-aza-2'deoxycytidine (5-aza-dC) and the histone deacetlyase (HDAC) inhibitor valproic acid (VPA) efficiently prevented MB and RMS formation, whereas monotherapies with either drug were less effective. Wild-type Ptch expression was efficiently reactivated in tumors by 5-aza-dC/VPA combination therapy. This was associated with reduced methylation of the Ptch promoter and induction of histone hyperacetylation suggesting inhibition of HDACs in vivo. However, the treatment was not effective in clinically overt, advanced stage tumors. This is a first in vivo demonstration that targeting of Dnmt and HDAC activities is highly effective in preventing formation of Ptch-associated tumors. The results suggest a novel clinical strategy for consolidation therapy of corresponding tumors in humans after completion of conventional treatment. Our data also suggest that epigenetic therapy may be less effective in treating advanced stages of tumors, at least in this tumor model.


Twitter sentiment classification for measuring public health concerns.
An important task of public health officials is to keep track of health issues, such as spreading epidemics. In this paper, we are addressing the issue of spreading public concern about epidemics. Public concern about a communicable disease can be seen as a problem of its own. Keeping track of trends in concern about public health and identifying peaks of public concern are therefore crucial tasks. However, monitoring public health concerns is not only expensive with traditional surveillance systems, but also suffers from limited coverage and significant delays. To address these problems, we are using Twitter messages, which are available free of cost, are generated world-wide, and are posted in real time. We are measuring public concern using a two-step sentiment classification approach. In the first step, we distinguish Personal tweets from News (i.e., Non-Personal) tweets. In the second step, we further separate Personal Negative from Personal Non-Negative tweets. Both these steps consist themselves of two sub-steps. In the first sub-step (of both steps), our programs automatically generate training data using an emotion-oriented, clue-based method. In the second sub-step, we are training and testing three different Machine Learning (ML) models with the training data from the first sub-step; this allows us to determine the best ML model for different datasets. Furthermore, we are testing the already trained ML models with a human annotated, disjoint dataset. Based on the number of tweets classified as Personal Negative, we compute a Measure of Concern (MOC) and a timeline of the MOC. We attempt to correlate peaks of the MOC timeline to peaks of the News (Non-Personal) timeline. Our best accuracy results are achieved using the two-step method with a Naïve Bayes classifier for the Epidemic domain (six datasets) and the Mental Health domain (three datasets).


Principal Factors Associated With Ketorolac-Refractory Pain Behavior After Pediatric Myringotomy and Pressure Equalization Tube Placement: A Retrospective Cohort Study.
Prophylactic analgesic administration reduces pain behavior after pediatric bilateral myringotomy and pressure equalization tube placement (BMT). We hypothesized that postoperative pain in children treated with intraoperative ketorolac would, among several exposures of interest, be strongly associated with ear condition. We conducted a retrospective cohort study of healthy children (9 months to 7 years) who underwent BMT at the Children's Hospital of Philadelphia or its ambulatory surgery centers from 2013 to 2016. Anesthetic care included preoperative oral midazolam, sevoflurane/nitrous oxide (N2O)/air/oxygen (O2) by mask, and intramuscular ketorolac. Demographic and procedural information included left and right tympanic membrane (normal, retracted, or bulging) and middle ear (normal/no, serous, mucoid, or purulent effusion) conditions. Because tympanic membrane and middle ear conditions were highly concordant and mean maximum Face, Legs, Activity, Cry and Consolability (FLACC) scores (0-10) were not different across the array of abnormal findings, we categorized each ear as normal or abnormal based on middle ear effusion alone. We then defined the ear condition of each child (primary exposure) using bilateral findings: normal/normal, normal/abnormal, and abnormal/abnormal. Secondary exposures included age, BMT history, procedure duration, facility location, and attending surgeon/anesthesiologist pair. The primary outcome was maximum postanesthesia care unit FLACC score: 4-10 (moderate-to-severe pain) versus 0-3 (no-to-low pain). Rescue oxycodone, acetaminophen administration, and emergence agitation were secondary outcomes. Statistical analysis incorporated generalized linear mixed models with random intercepts accounting for the clustering effect of provider pairs. Adjusting for multiple comparisons, significance level was set at P = .004. Excluding recurrent cases, 1922 unique evaluable subjects remained. The probability of moderate-to-severe pain behavior (FLACC, 4-10) was 52.4% (95% confidence interval [CI], 50.2-54.6) overall. In a confounder-adjusted model, ear condition was significantly associated with moderate-to-severe pain: compared to bilateral abnormal (effusions), odds ratio (OR) (95% CI) for bilateral normal was 2.2 (1.6-2.9), P < .0001. Younger age (OR, 1.1 [1.1-1.2] per year; P = .001) and longer procedure duration (OR, 1.1 [1.0-1.2] per minute; P = .0008) were likewise related to higher pain. With surgeon added to the model, variance explained by provider pairs decreased from 9.60% to 1.05%. Two secondary outcome associations also emerged: comparing bilateral normal to abnormal ears, ORs were 1.7 (1.3-2.2), P = .0001, for rescue oxycodone and 2.0 (1.2-3.3), P = .008, for emergence agitation. Pain behavior after BMT varies by surgeon and is strongly associated with ear condition. Ketorolac as a single prophylactic analgesic appears less effective in younger children with normal middle ear findings.


Dynamic density shaping of photokinetic E. coli.
Many motile microorganisms react to environmental light cues with a variety of motility responses guiding cells towards better conditions for survival and growth. The use of spatial light modulators could help to elucidate the mechanisms of photo-movements while, at the same time, providing an efficient strategy to achieve spatial and temporal control of cell concentration. Here we demonstrate that millions of bacteria, genetically modified to swim smoothly with a light controllable speed, can be arranged into complex and reconfigurable density patterns using a digital light projector. We show that a homogeneous sea of freely swimming bacteria can be made to morph between complex shapes. We model non-local effects arising from memory in light response and show how these can be mitigated by a feedback control strategy resulting in the detailed reproduction of grayscale density images.


Molecular, functional and evolutionary characterization of the gene encoding HMG-CoA reductase in the fission yeast, Schizosaccharomyces pombe.
The synthesis of mevalonate, a molecule required for both sterol and isoprene biosynthesis in eukaryotes, is catalysed by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Using a gene dosage approach, we have isolated the gene encoding HMG-CoA reductase hmgl+, from the fission yeast Schizosaccharomyces pombe (Accession Number L76979). Specifically, hmgl+ was isolated on the basis of its ability to confer resistance to lovastatin, a competitive inhibitor of HMG-CoA reductase. Gene disruption analysis showed that hmgl+ was an essential gene. This result provided evidence that, unlike Saccharomyces cerevisiae, S. pombe contained only a single functional HMG-CoA reductase gene. The presence of a single HMG-CoA reductase gene was confirmed by genomic hybridization analysis. As observed for the S. cerevisiae HMGlp, the hmgl+ protein induced membrane proliferations known as karmellae. A previously undescribed 'feed-forward' regulation was observed in which elevated levels of HMG-CoA synthase, the enzyme catalysing the synthesis of the HMG-CoA reductase substrate, induced elevated levels of hmgl+ protein in the cell and conferred partial resistance to lovastatin. The amino acid sequences of yeast and human HMG-CoA reductase were highly divergent in the membrane domains, but were extensively conserved in the catalytic domains. We tested whether the gene duplication that produced the two functional genes in S. cerevisiae occurred before or after S. pombe and S. cerevisiae diverged by comparing the log likelihoods of trees specified by these hypotheses. We found that the tree specifying post-divergence duplication had significantly higher likelihood. Moreover, phylogenetic analyses of available HMG-CoA reductase sequences also suggested that the lineages of S. pombe and S. cerevisiae diverged approximately 420 million years ago but that the duplication event that produced two HMG-CoA reductase genes in the budding yeast occurred only approximately 56 million years ago. To date, S. pombe is the only unicellular eukaryote that has been found to contain a single HMG-CoA reductase gene. Consequently, S. pombe may provide important opportunities to study aspects of the regulation of sterol biosynthesis that have been difficult to address in other organisms and serve as a test organism to identify novel therapies for modulating cholesterol synthesis.


Short-term effects of antipsychotic treatment on cerebral function in drug-naive first-episode schizophrenia revealed by "resting state" functional magnetic resonance imaging.
Most of what we know about antipsychotic drug effects is at the receptor level, distal from the neural system effects that mediate their clinical efficacy. Studying cerebral function in antipsychotic-naive patients with schizophrenia before and after pharmacotherapy can enhance understanding of the therapeutic mechanisms of these clinically effective treatments. To examine alterations of regional and neural network function in antipsychotic-naive patients with first-episode schizophrenia before and after treatment with second-generation antipsychotic medication. Case-control study. Huaxi MR Research Center and Mental Health Centre of the West China Hospital. Thirty-four antipsychotic-naive patients with first-episode schizophrenia were scanned using gradient-echo echo-planar imaging while in a resting state. After 6 weeks of antipsychotic treatment, patients were rescanned. Thirty-four matched healthy control subjects were studied at baseline for comparison purposes. The amplitude of low-frequency fluctuations (ALFF) of blood oxygen level-dependent signals, believed to reflect spontaneous neural activity, was used to characterize regional cerebral function. Functional connectivity across brain regions was evaluated using a seed voxel correlation approach and an independent component analysis. Changes in these measures after treatment were examined to characterize effects of antipsychotic drugs on regional function and functional integration. After short-term treatment with second-generation antipsychotic medications, patients showed increased ALFF, particularly in the bilateral prefrontal and parietal cortex, left superior temporal cortex, and right caudate nucleus. Increased regional ALFF was associated with a reduction of clinical symptoms, and a widespread attenuation in functional connectivity was observed that was correlated with increased regional ALFF. We demonstrate for the first time, to our knowledge, that widespread increased regional synchronous neural activity occurs after antipsychotic therapy, accompanied by decreased integration of function across widely distributed neural networks. These findings contribute to the understanding of the complex systems-level effects of antipsychotic drugs.


Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism.
We investigated expression of gamma-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABA(B) receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABA(B) receptor pathway using GABA(B) receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABA(A) receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA(B) receptor pathway may be involved in the process.


Complement activation by cholesterol crystals triggers a subsequent cytokine response.
In the host a diverse collection of endogenous danger signals is constantly generated consisting of waste material as protein aggregates or crystalline materials that are recognized and handled by soluble pattern recognition receptors and phagocytic cells of the innate immune system. These signals may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation. CC is recognized by the lectin- and classical pathways of the complement system resulting in activation of C3 and C5 with release of inflammatory mediators like the potent C5a fragment. Complement activation by CC leads to crosstalk with the NLRP3 inflammasome-caspase-1 pathway and production of IL-1β. Neutralization of IL-1β may have beneficial effects on atherosclerosis and a large clinical trial with an IL-1β inhibitor is currently in progress (the CANTOS study). However, upstream inhibition of CC-induced inflammation by using a complement inhibitor may be more efficient in treating atherosclerosis since this will block initiation of inflammation processes before downstream release of cytokines including IL-1β. Another therapeutic candidate can be broad-acting 2-hydroxypropyl-β-cyclodextrin, a compound that targets several mechanisms such as cholesterol efflux, complement gene expression, and the NLRP3 pathway. In summary, emerging evidence show that complement is a key upstream player in the pathophysiology of atherosclerosis and that therapy aiming at inhibiting complement could be effective in controlling atherosclerosis.


TMS Motor Thresholds Correlate With TDCS Electric Field Strengths in Hand Motor Area.
Transcranial direct current stimulation (TDCS) modulates cortical activity and influences motor and cognitive functions in both healthy and clinical populations. However, there is large inter-individual variability in the responses to TDCS. Computational studies have suggested that inter-individual differences in cranial and brain anatomy may contribute to this variability via creating varying electric fields in the brain. This implies that the electric fields or their strength and orientation should be considered and incorporated when selecting the TDCS dose. Unfortunately, electric field modeling is difficult to perform; thus, a more-robust and practical method of estimating the strength of TDCS electric fields for experimental use is required. As recent studies have revealed a relationship between the sensitivity to TMS and motor cortical TDCS after-effects, the aim of the present study was to investigate whether the resting motor threshold (RMT), a simple measure of transcranial magnetic stimulation (TMS) sensitivity, would be useful for estimating TDCS electric field strengths in the hand area of primary motor cortex (M1). To achieve this, we measured the RMT in 28 subjects. We also obtained magnetic resonance images from each subject to build individual three-dimensional anatomic models, which were used in solving the TDCS and TMS electric fields using the finite element method (FEM). Then, we calculated the correlation between the measured RMT and the modeled TDCS electric fields. We found that the RMT correlated with the TDCS electric fields in hand M1 (R2 = 0.58), but no obvious correlations were identified in regions outside M1. The found correlation was mainly due to a correlation between the TDCS and TMS electric fields, both of which were affected by individual's anatomic features. In conclusion, the RMT could provide a useful tool for estimating cortical electric fields for motor cortical TDCS.


Differential expression of cytochrome c oxidase subunit III gene in castes of the termite Reticulitermes santonensis.
Social insects such as termites live in colonies in which cooperation is assumed by all individuals developing into castes to which specific tasks are allocated. Little has been reported about molecular aspects underlying termite caste-specific gene expression. Genetic regulation has recently been hypothesized to govern caste-specific traits and physiology in social insects. Cytochrome c oxidase (COX) has been shown to be an interesting candidate for expression study in insects. We used the cytochrome c oxidase subunit III gene (COXIII) that was cloned from mRNA in a lower termite, Reticulitermes santonensis De Feytaud (Isoptera; Rhinotermitidae). The full-length cDNA encodes a protein of 262 amino acids that shows high degree of homology with other insects COXIIIs. Reverse transcriptase-PCR and real-time PCR were performed to compare gene expression between larvae, workers, nymphs and soldiers. Analyses performed on head cDNAs revealed that COXIII is differentially expressed between castes. The level of COXIII is caste-regulated with an increase in workers (approximately 1.9-fold) and nymphs (approximately 2.8-fold) and a decrease in soldiers (0.8-fold) compared to the expression level in larvae (1.0-fold). These results may emphasize the physiological importance of COX in the termite brain at different developmental stages.


Multi-method brain imaging reveals impaired representations of number as well as altered connectivity in adults with dyscalculia.
Two hypotheses have been proposed about the etiology of neurodevelopmental learning disorders, such as dyslexia and dyscalculia: representation impairments and disrupted access to representations. We implemented a multi-method brain imaging approach to directly investigate these representation and access hypotheses in dyscalculia, a highly prevalent but understudied neurodevelopmental disorder in learning to calculate. We combined several magnetic resonance imaging methods and analyses, including univariate and multivariate analyses, functional and structural connectivity. Our sample comprised 24 adults with dyscalculia and 24 carefully matched controls. Results showed a clear deficit in the non-symbolic magnitude representations in parietal, temporal and frontal regions, as well as hyper-connectivity in visual brain regions in adults with dyscalculia. Dyscalculia in adults was thereby related to both impaired number representations and altered connectivity in the brain. We conclude that dyscalculia is related to impaired number representations as well as altered access to these representations.