Development of a fast and simple gas chromatographic protocol based on the combined use of alkyl chloroformate and solid phase microextraction for the assay of polyamines in human urine.
Polyamines are aliphatic amines with low molecular weight that are widely recognized as one of the most important cancer biomarkers for early diagnosis and treatment. The goal of the work herein presented is the development of a rapid and simple method for the quantification of free polyamines (i.e., putrescine, cadaverine, spermidine, spermine) and N-monoacetylated polyamines (i.e., N1-Acetylspermidine, N8-Acetylspermidine, and N1-Acetylspermine) in human urine. A preliminary derivatization with propyl chloroformate combined with the use of solid phase microextraction (SPME) allowed for an easy and automatable protocol involving minimal sample handling and no consumption of organic solvents. The affinity of the analytes toward five commercial SPME coatings was evaluated in univariate mode, and the best result in terms of analyte extraction was achieved using the divinylbenzene/carboxen/polydimethylsiloxane fiber. The variables affecting the performance of SPME analysis were optimized by the multivariate approach of experimental design and, in particular, using a central composite design (CCD). The optimal working conditions in terms of response values are the following: extraction temperature 40 °C, extraction time of 15 min and no addition of NaCl. Analyses were carried out by gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS) in selected reaction monitoring (SRM) acquisition mode. The developed method was validated according to the guidelines issued by the Food and Drug Administration (FDA). The satisfactory performances reached in terms of linearity, sensitivity (LOQs between 0.01 and 0.1 μg/mL), matrix effect (68-121%), accuracy, and precision (inter-day values between -24% and +16% and in the range 3.3-28.4%, respectively) make the proposed protocol suitable to be adopted for quantification of these important biomarkers in urine samples.


[Development of a Real-Time Reverse Transcription PCR Assay System for Detection of Three Subtypes of Influenza A and Influenza B Viruses].
We developed the initial real-time reverse transcription PCR assay system for seasonal influenza viruses in 2011. This prototype assay system could detect and identify specific influenza A virus subtypes[H1N1, H3N2 and (H1N1) pdm09] and influenza B virus. In the 2012-2013 season, our prototype PCR assay didn't work well because of point mutations occurred in the neuraminidase (NA) gene of the A (H3N2) strain. We improved the prototype assay by changing the target gene for A (H3N2) strain (2013 improved PCR assay). Moreover, we added the measurement system for the matrix (M) gene that was well conserved and common to all influenza A subtypes. In the 2013-2014 season, point mutations in the hemagglutinin (HA) gene of the A (H1N1) pdm09 strain lowered the sensitivity of the 2013 improved PCR assay, so that we changed the target gene for A (H1N1)pdm09 strain (2014 improved PCR assay). We analyzed swab samples from 1,721 patients in total by at least one of the three PCR assays we developed, and demonstrated that the PCR assays had excellent sensitivity and specificity compared with those of the commercially available rapid immunochromatography kit we used. In this study, the M gene was positive in all patients who were finally diagnosed as influenza A positive by 2013 or 2014 improved PCR assay. Therefore, measurement of the M gene, which is hardly to be affected by antigenic drift of influenza viruses, is thought to be useful in clinical practice.


Three-dimensional foveal shape changes after asymptomatic macular posterior vitreous detachment.
To show a case in which the shape of the fovea changed after an asymptomatic macular posterior vitreous detachment (PVD). The foveal shape was determined from the spectral-domain optical coherence tomography (OCT) images before and after a spontaneous macular PVD. A 66-year-old man with a unilateral macular hole in the right eye presented with a perifoveal PVD in the asymptomatic left eye. One year later, the left eye developed a macular PVD, and OCT measurements showed a 16.7% decrease in the central foveal thickness, and increases in the pit depth by 20.5%, foveola diameter by 14.7%, and pit volume by 19.4%. The thicknesses of the macular subfields of the Early Treatment Diabetic Retinopathy Study were decreased by 13.0% in the central subfield and by 1.4%-6.6% in the other subfields. The deepening and widening of the fovea after a macular PVD indicate that a PVD can alter the shape of the fovea.


Catalysis using gold nanoparticles decorated on nanocrystalline cellulose.
A novel nanocomposite was prepared by deposition of carbonate-stabilized Au nanoparticles (AuNPs) onto the surface of poly(diallyldimethyl ammonium chloride) (PDDA)-coated carboxylated nanocrystalline cellulose (NCC). The hybrid material possessed AuNPs (1.45% by weight) with an average diameter of 2.95 ± 0.06 nm. The catalytic activity of AuNP/PDDA/NCC for reducing 4-nitrophenol to 4-aminophenol was compared to other Au-supported composites. An activation energy of 69.2 kJ mol(-1) was obtained for the reaction. Indeed, the reaction rate constant k of (5.1 ± 0.2) × 10(-3) s(-1) was comparable to the benchmark literature value obtained using AuNPs (<5 nm in diameter) decorated on a network of crystalline cellulose fibers. Our strategy promotes the use of natural resources to prepare reusable hybrid inorganic-organic materials for important reactions with facilitated product isolation/purification.


[Abnormal expression of caspase8,bcl-2 and cytochrome C in drug resistant lung cancer cell].
To investigate the relations between the chemotherapy resistance in lung cancer cell (LCC) A549 and the expression of apoptosis protein including caspase8, bcl-2 and cytochrome C and bcl-2 mRNA. Bcl-2 mRNAs of sensitive A549 cell (A549S) and drug-resistant A549 cell (A549R) cultured were amplified by reverse transcription polymerase chain reaction (RT-PCR), and the expressions in the two strains were compared by AG electrophoresis, with beta-actin as control. The caspase8, bcl-2 and cytochrome C proteins in the two strains were measured and assessed by Western Blot. The caspase8 and cytochrome C protein expressions were higher in A459S than in A549R (P<0.05). The bcl-2 protein expression was lower in A459S than in A549R (P<0.05). But there was no significant difference between the level of bcl-2 mRNA expression in strain A549S (8.74+/-1.81) and that in strain A549R (10.29+/-2.92) (P>0.05). The upregulation of the bcl-2 protein could depress the caspase8 and cytochrome C protein expression and so might be one of the reasons for drug resistance in lung cancer cell, but the upregulation might happen at the level of translation or thereafter not at the mRNA level.


A Cross-Sectional Study of Quality of Life among Subjects with Epilepsy Attending a Tertiary Care Hospital.
Epilepsy is a chronic disorder associated with profound physical and psychological consequences leading to impaired quality of life (QoL). Evaluation of the QoL among epileptics would throw light on various factors that impair or affect the QoL in such a population. To study the QoL among epileptic patients attending outpatient departments of a tertiary care hospital and to identify various factors that affect the QoL in such a population. A cross-sectional observational questionnaire based study, including patients with epilepsy, who were on antiepileptic drugs, on follow-up for minimum one year, aged more than 18years, both sexes and who were seizure free in the previous 24hours. The World Health Organisation Quality of Life (WHOQOL-BREF) questionnaire was administered to those included in the study. The data was analysed using Statistical Package for Social Sciences (SPSS) version 20 and statistical tests like t-test for independent variables and Analysis of Variance (ANOVA) were used to compare the QoL scores. Of the 98 subjects 61.2% were males, majority were educated upto high school level and most of them were employed in unskilled labour. The mean total QOL score was 53.9 (15.8). There was a significant lower mean total QOL score among people with low educational status and poor seizure control. Epilepsy is a syndrome associated with chronic drug use and regular long term follow-ups to hospitals. These treatment and disease associated problems affects the QOL of the subjects significantly in various squares of life. We found that a lower education and having seizure in the recent past affected the QOL scores.


Utilization of Hospice Bereavement Support by At-Risk Family Members.
Approximately 10% of the bereaved are at risk of bereavement-related mental health disorders. Hospices' bereavement services could potentially address needs of many at risk, but little is known about their service use. We analyzed data from 6160 bereaved family members of hospice patients. Risk of mental health problems was identified by hospice providers postloss. Of those characterized as "at-risk," 52% used services compared to 18% of the "low risk." Factors associated with service use among at-risk were female gender and younger age of death. Those who lost a child used services less than other bereaved. Although hospices appear to be skilled at identifying and providing bereavement services to the at-risk, services do not reach almost half. Results suggest the need to improve care access, especially among men and those losing a child.


Photosynthetic Genes of Petunia (Mitchell) Are Differentially Expressed during the Diurnal Cycle.
The petunia (Petunia [Mitchell]) chloroplast proteins, the chlorophyll a/b-binding (Cab) proteins, and the small subunit of ribulose bisphosphate carboxylase (RbcS) are encoded by nuclear genes that are expressed in a light-dependent manner. The steady-state concentrations of five cab mRNAs vary with a dramatic circadian rhythm in plants grown under a constant diurnal cycle (10 hours light, 14 hours dark). cab mRNA levels reach their maximum during the light period, but begin to drop prior to the dark period. These RNAs fall to their minimum concentration during the dark period and then begin to increase again in anticipation of the light. Within this general pattern, there are variations in expression among specific classes of cab genes. The light harvesting complex of photosystem II LHCII-type 1 cab mRNAs rise to a well-defined maximum at 2 hours prior to the dark period. All but one of these genes are expressed in anticipation of the light period. The LHCII type 2 cab mRNA and the LHC of photosystem I cab mRNA are expressed at more constant levels throughout the light period. The expression of these genes anticipates the light more than does the expression of the LHCII type 1 genes. The steady state mRNA levels for the petunia rbcS genes show no significant diurnal fluctuation.


More atrophy of deep gray matter structures in frontotemporal dementia compared to Alzheimer's disease.
The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer's disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of hippocampus, amygdala, thalamus, caudate nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1-weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD.


[Evaluation of interaction between drugs and ordered phospholipid membrane by immobilized artificial membrane chromatography].
To investigate the interaction between drugs and ordered phospholipid membrane using immobilized artificial membrane chromatography (IAMC). IAMC was used to determine the interaction drugs with phospholipid membrane, expressed as membrane affinity (lg kIAM). An n-octanol/buffer system was also employed as the reference hydrophobicity (lg Do/w,7.4). Within the range of used acetonitrile percentages (phi) 0-30% in mobile phase, retention index (lg kIAM) showed excellent correlation with phi. Intercepts of fitted straight lines between lg kIAM and phi were comparable but slopes were much different for the three organic modifiers (acetonitrile, ethanol and methanol). Effects by adding CH2 substituent on lipophilicity difference (delta lg kIAM and delta lg Do/w,7.4) were similar for p-hydroxyl benzoic methyl ester to butyl ester, whereas different for p-hydroxylbenzoic acid to methyl ester. IAMC system is a convenient, efficient and rapid tool for determining membrane interaction.


Evidence for the accumulation of peroxidized lipids in membranes of senescing cotyledons.
Fluorescent products of lipid peroxidation accumulate with age in microsomal membranes from senescing cotyledons of Phaseolus vulgaris. The temporal pattern of accumulation is closely correlated with a rise in the lipid phase transition temperature reflecting the formation of gel phase lipid. Increased levels of fluorescent peroxidation products are also detectable in total lipid extracts of senescent cotyledons. Lipoxygenase activity increases with advancing age by about 3-fold on a fresh weight basis and 4-fold on a dry weight basis indicating that the tissue acquires elevated levels of lipid hydroperoxides. As well, levels of glutathione and superoxide dismutase activity decline on a dry weight basis as the cotyledons age, rendering the tissue more susceptible to oxidative damage. Catalase activity rises initially and then declines during senescence, but peroxidase activity rises steeply. Thus, apart from this increase in peroxidase, which would scavenge H(2)O(2) only if appropriate cosubstrates were available, the defense mechanisms for coping with activated oxygen species (O(2) (-), H(2)O(2), OH) are less effective in the older tissue. The observations support the contention that formation of gel phase lipid in senescing membranes is attributable to lipid peroxidation and suggest that the reactions of lipid peroxidation are utilized by the cotyledons to mediate deteriorative changes accompanying the mobilization and transport of metabolites from the storage tissue to the developing embryo.


Species-specific PCR for the identification of ovine, porcine and chicken species in meta and bone meal (MBM).
BSE, first identified in the UK in 1986 is thought to have arisen from feeding scrapie infected Meat and Bone Meal (MBM), produced under sub-optimal conditions, to cattle. For quality and safety reasons there is a requirement for a good analytical test for the surveillance of processed MBM. This study describes species-specific PCR assays for the identification of ovine, porcine and poultry species in MBM. A comparison between two distinct DNA extraction methods, i.e. the silicaguanidiumthiocyanate DNA isolation procedure and a commercial DNA extraction kit, is also presented. Application of this technology to species identification in industrial MBM was investigates as part of this study.


A constraint-based approach to modelling the mobility of the human knee joint.
A model of knee mobility able to predict the range and pattern of movement in the unloaded joint was proposed by Wilson et al. (J. Biomech. 31 (1998) 1127-1136). The articular surfaces in the lateral and medial compartments and isometric fascicles in three of the knee ligaments were represented as five constraints on motion between the femur and tibia in a single degree-of-freedom parallel spatial mechanism. The path of movement of the bones during passive flexion was found by solving the forward kinematics of the mechanism using an iterative method. The present paper shows that such a mechanism-based solution approach can lead to an underestimation of the flexion range. This is due to the mechanism reaching a 'stationary configuration' and 'locking'. A new, constraint-based approach to the solution of the model joint displacement is proposed. It avoids the representation of ligaments and articular surfaces by kinematically equivalent chains of one degree-of-freedom pairs which are prone to singularities. It relies instead on a numerical solution of five non-linear constraint equations to find the relative positions of the bones at a series of flexion angles. The method is successful both in its ability to predict motion through a physiological range and in its efficiency with a solution rate forty times faster than the original algorithm. The new approach may be extended to include more complex joint surface geometry, allowing a study of the effects of articular surface shape and ligament arrangement on joint kinematics.


Ethrel (Ethylene Releaser)-Induced Increases in the Adenylate Pool and Transtonoplast DeltapH within Hevea Latex Cells.
The treatment of rubber tree (Hevea brasiliensis) bark with chloro-2-ethyl phosphonic acid (ethrel), an ethylene-releasing chemical, induced, after a lag period of 13 to 21 hours, a marked increase in the total adenine nucleotides (essentially ATP and ADP) of latex cells. This rise in the latex adenylate pool was concomitant with a marked decrease in the [ATP]/[ADP] ratio without significant changes in the adenylate energy charge. The apparent equilibrium constant for the adenylate kinase, which appeared to behave as a key enzyme in maintaining the adenylate energy charge in the latex, was considerably reduced, probably as a consequence of the alkalinization of the latex cytosol induced by the treatment with ethrel. To reduce the "sink effect" and activation of the metabolism induced in Hevea bark by regular tapping, the latex was collected by micropuncture (few drops) at increasing distance (5-50 centimeters) above and below an ethrel-treated area on the virgin bark of resting trees. The effect of ethrel was shown to spread progressively along the trunk. The increase in the adenylate pool (essentially ATP) was detectable as early as 24 hours after the bark treatment and was maximum after 6 or 8 days, 5 centimeters as well as 50 centimeters above and below the stimulated bark ring. The correlative vacuolar acidification and cytosolic alkalinization, i.e. the increase in the transtonoplast DeltapH, induced in the latex cells by ethrel were shown to be concomitant with the rise in ATP content of the latex. This suggests that the tonoplast H(+)-pumping ATPase, which catalyzes vacuolar acidification in the latex, is directly and essentially under the control of the availability of its substrate (i.e. ATP) in the latex. The results are discussed in relation to energy-dependent activation of metabolism, and increased rubber production, as induced by the stimulation of rubber trees with ethrel.


Determination of Traditional and Designer Benzodiazepines in Urine through LC-MS/MS.
The detection of new designer benzodiazepines in biological fluids and tissues, together with the traditional ones, could represent an important analytical update for laboratories performing clinical and forensic toxicological analysis. A liquid chromatography tandem mass spectrometry method (LC-MS/MS) has been developed, fully validated, and applied to a cohort of real urine samples collected from patients under withdrawal treatment and from intoxication cases. 100 μL urines were added to a buffer solution containing deuterated internal standards; the samples were then extracted through a liquid/liquid procedure, dried under a nitrogen stream, and reconstituted in mobile phase. The chromatographic separation was performed in reverse phase through a C18 column with gradient elution. Mass spectrometry operated in positive polarization and multiple reaction monitoring mode. 25 molecules were optimized for instrumental analysis: 9 designer benzodiazepines and 16 traditional compounds (parent drugs and main metabolites). Sensitivity, specificity, linearity, accuracy, imprecision, recovery, matrix effects, and carry-over have been evaluated for all molecules. Only cinazepam did not satisfy all acceptance criteria for validation. 10 among the 50 analyzed samples tested positive for at least one of the monitored molecules. In particular, two different samples collected from the same case provided positive results for flubromazepam, a designer benzodiazepine. The method was proven to be useful in detecting not only traditional benzodiazepines but also new designer ones. The identification of a New Psychoactive Substance in real samples confirmed that analytical procedures should be updated to include as many substances as possible.


Relationship between dental caries and total joint arthroplasty at a Veterans Administration hospital.
It has previously been suspected that patients who undergo extensive dental procedures after having had a total joint arthroplasty (TJA) within the preceding 2 years may be at risk for seeding their TJA with infection if prophylaxis antibiotic coverage is not implemented one hour prior to the dental procedure. A review of the literature was performed to determine whether there may be other infections which may be accountable for TJA infections within the first 2 years following a TJA. Patients with systemic diseases, those who undergo extensive dental procedures, those with bladder or skin infection were found to be at risk for development of a TJA if prophylactic antibiotic therapy was not implemented in a timely manner.


Patterns of salivary cortisol secretion and responses to daily events in patients with remitted bipolar disorder.
Previous studies on bipolar disorder revealed abnormalities in the function of the HPA axis, including disturbed patterns of cortisol secretion, during depressive and manic episodes. It is less clear whether these abnormalities persist after symptomatic recovery. In the present study we used the experience sampling method with intensive salivary cortisol sampling to study patterns of cortisol secretion in relation to negative and positive daily events during the normal daily life of a group of 36 patients with remitted bipolar disorder and 38 healthy controls. Results of multilevel regression analysis indicated that daytime cortisol levels and reactivity to daily events were similar in remitted bipolar patients and healthy controls, but bipolar patients showed flatter diurnal slopes and larger cortisol fluctuations over successive measures. Patients with many previous episodes had higher overall cortisol levels, reduced cortisol reactivity to negative daily events, and flatter diurnal slopes than patients with fewer episodes. These results provide additional evidence of subtle HPA axis dysregulation in remitted bipolar patients, especially in those with many recurrent episodes.


The Odyssey of Episodic Memories: Identifying the Paths and Processes Through Which They Contribute to Well-Being.
This research highlights the processes through which lasting episodic memories and their characterized level of need satisfaction (autonomy, competence, and relatedness) can impact well-being, both at the situational level and over time. Study 1 (N = 92, Mage = 42.07 years, 72% female) investigated the effect of the unconscious activation of a personal episodic memory on situational well-being using a subliminal priming procedure. Study 2 (N = 275, Mage = 22.45 years, 84% female) followed the odyssey of an episodic memory by examining at various points over time its abstraction into perceptions of general need satisfaction and its long-term effect on well-being. Study 1 revealed that the activation of a need-satisfying memory produced an immediate increase in well-being, whereas the triggering of a need-thwarting memory led to an immediate decrease in well-being compared to controls. Study 2 revealed little influence of individual differences, but need satisfaction in episodic memories had a significant cumulative impact on well-being at different points in time over months and was abstracted into greater perceptions of general need satisfaction over time. Results provide convincing evidence for the directive function of memories on well-being, both at the situational level and over time.


Ionizing radiation affects profile of serum metabolites: increased level of 3-hydroxybutyric acid in serum of cancer patients treated with radiotherapy.
Radiotherapy causes molecular changes observed at the level of body fluids, which are potential biomarker candidates for assessment of radiation exposure. Here we analyzed radiotherapy-induced changes in a profile of small metabolites detected in sera of head and neck cancer patients using the gas chromatography coupled with mass spectrometry approach. There were about 20 compounds, including carboxylic acids, sugars, amines and amino acids, whose levels significantly differed between pre-treatment and post-treatment samples. Among metabolites upregulated by radiotherapy there was 3-hydroxybutyric acid, whose level increased about three times in post-treatment samples. Moreover, compounds affected by irradiation were associated with several metabolic pathways, including protein biosynthesis and amino acid metabolism.


Development of Guanidine-Bisurea Bifunctional Organocatalysts with a Chiral Pyrrolidine Moiety and Application to α-Hydroxylation of Tetralone-Derived β-Keto Esters.
Novel guanidine-bisurea bifunctional organocatalysts 5 bearing a chiral pyrrolidine moiety on guanidine were designed with the guidance of DFT calculations. The resulting organocatalysts 5 were examined for α-hydroxylation of tetralone-derived β-keto esters, and good selectivity was obtained with 5j bearing a methoxymethyl ether-containing chiral pyrrolidine moiety.


Dengue infection among tribal population in the Nilgiris district, Tamil Nadu, India.
Dengue emerged as an important public health problem in Tamil Nadu from 2000 onwards, reported in all the districts as an endemic disease of Tamil Nadu except Nilgiris district. So this study was carried out to understand the dengue epidemiology in Nilgiris district. Block-wise study was made at the Nilgiris district. The clinicians at the Nilgiris Adivasi Welfare Association hospitals (NAWA) situated in Kotagiri, Kozhikarai and Primary Health Centers from Kunjpannai, Arayoor, and Soloor Mattam, examined and recorded symptoms and collected blood samples from the dengue-suspected patients. These samples were centrifuged at 4°C and stored. Serum samples (267 nos.) collected from dengue-suspected patients for two years period from 2014 to 2016 were screened for dengue infection. First year study conducted during 2014-15 showed 13 dengue positives (8.39%) mainly from Kotagiri block (9 nos. - 69.2%) and the second year study conducted during 2015-16 showed 12 dengue positives (10.71%) found mostly from Udagamandalam block (6 nos.- 50%). People belonging to 6 different tribes - Irular, Toda, Kota, Kurumba, Kattunaickan, and Paniya were found infected with dengue and more Irular positives were recorded in both the years (5 Irular-2014-15 & 11 Irular -2015-16). First year detected more female positives (92.3%) whereas the second year showed 5 males (41.7%) and 7 females (58.3%). This study unearthed the hidden disease dengue to be prevalent among the tribal community and emphasized the need for the establishment of a permanent dengue surveillance system with improved disease diagnostics, to initiate effective vector control efforts to stop dengue transmission from this hilly region.


Direct MinE-membrane interaction contributes to the proper localization of MinDE in E. coli.
Dynamic oscillation of the Min system in Escherichia coli determines the placement of the division plane at the midcell. In addition to stimulating MinD ATPase activity, we report here that MinE can directly interact with the membrane and this interaction contributes to the proper MinDE localization and dynamics. The N-terminal domain of MinE is involved in direct contact between MinE and the membranes that may subsequently be stabilized by the C-terminal domain of MinE. In an in vitro system, MinE caused liposome deformation into membrane tubules, a property similar to that previously reported for MinD. We isolated a mutant MinE containing residue substitutions in R10, K11 and K12 that was fully capable of stimulating MinD ATPase activity, but was deficient in membrane binding. Importantly, this mutant was unable to support normal MinDE localization and oscillation, suggesting that direct MinE interaction with the membrane is critical for the dynamic behavior of the Min system.


Neuropathogenesis of a highly pathogenic avian influenza virus (H7N1) in experimentally infected chickens.
In order to understand the mechanism of neuroinvasion of a highly pathogenic avian influenza virus (HPAIV) into the central nervous system (CNS) of chickens, specific pathogen free chickens were inoculated with a H7N1 HPAIV. Blood, cerebrospinal fluid (CSF), nasal cavity and brain tissue samples were obtained from 1 to 4 days post-inoculation (dpi) of infected and control chickens. Viral antigen topographical distribution, presence of influenza A virus receptors in the brain, as well as, the role of the olfactory route in virus CNS invasion were studied using different immunohistochemistry techniques. Besides, viral RNA load in CSF and blood was quantified by means of a quantitative real-time reverse transcription-polymerase chain reaction. Viral antigen was observed widely distributed in the CNS, showing bilateral and symmetrical distribution in the nuclei of the diencephalon, mesencephalon and rhombencephalon. Viral RNA was detected in blood and CSF at one dpi, indicating that the virus crosses the blood-CSF-barrier early during infection. This early dissemination is possibly favoured by the presence of Siaα2,3 Gal and Siaα2,6 Gal receptors in brain vascular endothelial cells, and Siaα2,3 Gal receptors in ependymal and choroid plexus cells. No viral antigen was observed in olfactory sensory neurons, while the olfactory bulb showed only weak staining, suggesting that the virus did not use this pathway to enter into the brain. The sequence of virus appearance and the topographical distribution of this H7N1 HPAIV indicate that the viral entry occurs via the haematogenous route, with early and generalized spreading through the CSF.


PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.
Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2-Δct ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p < 0.0001). Moreover, +68GA del/del and ins/del genotypes in imatinib-treated chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an allele dose-dependent manner. Platelet-derived growth factor receptor-α -909AA genotype is also associated with lower expression of platelet-derived growth factor receptor-α. The downregulation of platelet-derived growth factor receptor-α expression may play a causative role in imatinib-induced thrombocytopenia, a common side effect, in the subset of chronic myeloid leukemia patients with platelet-derived growth factor receptor-α +68 GA ins/del, +68 GA del/del, and -909C/A genotypes.


Scrub typhus outbreak, northern Thailand, 2006-2007.
During a scrub typhus outbreak investigation in Thailand, 4 isolates of O. tsutsugamushi were obtained and established in culture. Phylogenetic analysis based on the 56-kDa type-specific antigen gene demonstrated that the isolates fell into 4 genetic clusters, 3 of which had been previously reported and 1 that represents a new genotype.


Expression of a serine protease gene prC is up-regulated by oxidative stress in the fungus Clonostachys rosea: implications for fungal survival.
Soil fungi face a variety of environmental stresses such as UV light, high temperature, and heavy metals. Adaptation of gene expression through transcriptional regulation is a key mechanism in fungal response to environmental stress. In Saccharomyces cerevisiae, the transcription factors Msn2/4 induce stress-mediated gene expression by binding to the stress response element. Previous studies have demonstrated that the expression of extracellular proteases is up-regulated in response to heat shock in fungi. However, the physiological significance of regulation of these extracellular proteases by heat shock remains unclear. The nematophagous fungus Clonostachys rosea can secret an extracellular serine protease PrC during the infection of nematodes. Since the promoter of prC has three copies of the stress response element, we investigated the effect of environmental stress on the expression of prC. Our results demonstrated that the expression of prC was up-regulated by oxidants (H(2)O(2) or menadione) and heat shock, most likely through the stress response element. After oxidant treatment or heat shock, the germination of conidia in the wild type strain was significantly higher than that in the prC mutant strain in the presence of nematode cuticle. Interestingly, the addition of nematode cuticle significantly attenuated the production of reactive oxygen species (ROS) induced by oxidants and heat shock in the wild type strain, but not in prC mutant strain. Moreover, low molecule weight (<3 kD) degradation products of nematode cuticle suppressed the inhibitory effect of conidial germination induced by oxidants and heat shock. These results indicate that PrC plays a protective role in oxidative stress in C. rosea. PrC degrades the nematode cuticle to produce degradation products, which in turn offer a protective effect against oxidative stress by scavenging ROS. Our study reveals a novel strategy for fungi to adapt to environmental stress.


Effects of acute systemic endothelin receptor blockade on cardiac electrophysiology in vivo.
BQ-123, a selective endothelin-A receptor antagonist, has been demonstrated to suppress arrhythmias. However, the role of physiologic levels of endogenous endothelin-1 (ET-1) with respect to electrophysiologic properties of the heart is unknown. BQ-123 (0.45, 0.9, 1.8, 3.6, 7.2, and 14.4 microg/kg/min; n = 10) or saline (control, n = 5) was administered IV for 15 minutes of continuous-rate infusion at incremental doses to anesthetized normal pigs. BQ-123 had no effect on PR and QT interval, QRS duration, intraatrial and AV nodal conduction time as well as the atrial, AV nodal, and ventricular effective refractory periods. As compared with baseline, BQ-123 at 7.2 and 14.4 microg/kg/min caused an increase in heart rate (99 +/- 17 versus 110 +/- 14 and 118 +/- 14 bpm, respectively; P < 0.05), shortened sinus node recovery time (818 +/- 165 versus 641 +/- 69 and 609 +/- 74 milliseconds, respectively; P < 0.05) and decreased mean arterial pressure at 14.4 microg/kg/min (95 +/- 18 versus 80 +/- 11 mm Hg; P < 0.05). We conclude that in the normal pig, physiologic levels of ET-1 have no effect on conduction properties of atrial, AV nodal, or Purkinje fibers. However, antagonism of ET-1 by BQ-123 unmasks the effect of ET-1 on maintenance of vasomotor tone, which in turn may affect heart rate and sinus node automaticity in the intact pig.


Common origin for neutrino anarchy and charged hierarchies.
The generation of exponential flavor hierarchies from extra-dimensional wave function overlaps is reexamined. We find, surprisingly, that the coexistence of anarchic fermion mass matrices with such hierarchies is intrinsic and natural to this setting. The salient features of charged fermion and neutrino masses and mixings can thereby be captured within a single framework. Both Dirac and Majorana neutrinos can be realized. Implications for a variety of weak-scale scenarios, including warped compactification and supersymmetry, are discussed. When the new weak-scale physics is sensitive to the origin of flavor structure, Dirac neutrinos are preferred.


Effect of Picture-Book Reading With Additive Audio on Bilingual Preschoolers' Prefrontal Activation: A Naturalistic Functional Near-Infrared Spectroscopy Study.
Acquiring a second language (L2) has the power to shape cognition and even the function and structure of the brain. Picture-book reading with additive audio (PRA) is a popular and convenient means of providing L2 exposure for non-balanced bilingual children; however, its contribution to bilingual children's brain activity is unclear. This study conducted a rigorous bilingual word comprehension experiment and a naturalistic PRA task to explore the effect of L2 processing on brain activation among English as a foreign language (EFL) preschoolers, using functional near-infrared spectroscopy (fNIRS). We found that the two contexts of comprehending English words and bilingual switching (BS), which impose more cognitive control demands, activated the prefrontal cortex (PFC) more than did the condition of comprehending Chinese words. Furthermore, the effect of PFC activity in the condition of picture-book reading with additive English audio (English PRA) was also found to be greater than in the condition of picture-book reading with additive Chinese audio (Chinese PRA); moreover, the effect was modulated by story difficulty. Finally, a positive correlation was shown between EFL children's English competence and PFC activation through English PRA. This study indicates that the experiences of hearing L2 auditory stories in a picture-book reading activity yielded significant changes to early bilinguals' PFC functional for cognitive control and language processing.


The rational use of beta-adrenoceptor blockers in the treatment of heart failure. The changing face of an old therapy.
Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of antagonists of the adrenergic beta-receptor (beta-blockers) in heart failure has been the subject of debate for many years. Data from studies of the therapeutic use of beta-blockers in patients following acute myocardial infarction suggest that in this circumstance these agents confer at least as much benefit to patients with heart failure as they do to those without. Similarly retrospective analysis of a number of the studies of angiotensin converting enzyme (ACE) inhibitors in heart failure suggest a greater effect of the combination of beta-blocker with ACE inhibitor compared with ACE inhibitor alone. The results of recent prospective, placebo-controlled studies of the addition of beta-blocker to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect. beta-blocker therapy in these studies was well tolerated and in addition to improved mortality, beta-blocker therapy is associated with improved morbidity in terms of progressive heart failure and numbers of hospitalizations. Initiation of beta-blocker therapy in heart failure may be associated with deterioration of cardiac function in the short term. Treatment should be started at a low dose of beta-blocker with slow up-titration in a number of steps over several weeks. In spite of the established benefits of ACE inhibition in patients with heart failure, this treatment is under-utilized. Part of this shortfall is due to physicians' perceptions regarding potential unwanted effects of ACE inhibition. Perceptions regarding unwanted effects of beta-adrenoceptor blocker therapy are likely to be at least as great. While beta-blockade represents a welcome addition to the therapeutic armoury of physicians caring for patients with heart failure, initiation and stabilization of beta-adrenoceptor blocker therapy should be undertaken under specialist supervision.


The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives.
In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates.


Cognitive-behavioural interventions for attention deficit hyperactivity disorder (ADHD) in adults.
Attention deficit hyperactivity disorder (ADHD) is a developmental condition characterised by symptoms of inattention, hyperactivity and impulsivity, along with deficits in executive function, emotional regulation and motivation. The persistence of ADHD in adulthood is a serious clinical problem.ADHD significantly affects social interactions, study and employment performance.Previous studies suggest that cognitive-behavioural therapy (CBT) could be effective in treating adults with ADHD, especially when combined with pharmacological treatment. CBT aims to change the thoughts and behaviours that reinforce harmful effects of the disorder by teaching people techniques to control the core symptoms. CBT also aims to help people cope with emotions, such as anxiety and depression, and to improve self-esteem. To assess the effects of cognitive-behavioural-based therapy for ADHD in adults. In June 2017, we searched CENTRAL, MEDLINE, Embase, seven other databases and three trials registries. We also checked reference lists, handsearched congress abstracts, and contacted experts and researchers in the field. Randomised controlled trials (RCTs) evaluating any form of CBT for adults with ADHD, either as a monotherapy or in conjunction with another treatment, versus one of the following: unspecific control conditions (comprising supportive psychotherapies, no treatment or waiting list) or other specific interventions. We used the standard methodological procedures suggested by Cochrane. We included 14 RCTs (700 participants), 13 of which were conducted in the northern hemisphere and 1 in Australia.Primary outcomes: ADHD symptomsCBT versus unspecific control conditions (supportive psychotherapies, waiting list or no treatment)- CBT versus supportive psychotherapies: CBT was more effective than supportive therapy for improving clinician-reported ADHD symptoms (1 study, 81 participants; low-quality evidence) but not for self-reported ADHD symptoms (SMD -0.16, 95% CI -0.52 to 0.19; 2 studies, 122 participants; low-quality evidence; small effect size).- CBT versus waiting list: CBT led to a larger benefit in clinician-reported ADHD symptoms (SMD -1.22, 95% CI -2.03 to -0.41; 2 studies, 126 participants; very low-quality evidence; large effect size). We also found significant differences in favour of CBT for self-reported ADHD symptoms (SMD -0.84, 95% CI -1.18 to -0.50; 5 studies, 251 participants; moderate-quality evidence; large effect size).CBT plus pharmacotherapy versus pharmacotherapy alone: CBT with pharmacotherapy was more effective than pharmacotherapy alone for clinician-reported core symptoms (SMD -0.80, 95% CI -1.31 to -0.30; 2 studies, 65 participants; very low-quality evidence; large effect size), self-reported core symptoms (MD -7.42 points, 95% CI -11.63 points to -3.22 points; 2 studies, 66 participants low-quality evidence) and self-reported inattention (1 study, 35 participants).CBT versus other interventions that included therapeutic ingredients specifically targeted to ADHD: we found a significant difference in favour of CBT for clinician-reported ADHD symptoms (SMD -0.58, 95% CI -0.98 to -0.17; 2 studies, 97 participants; low-quality evidence; moderate effect size) and for self-reported ADHD symptom severity (SMD -0.44, 95% CI -0.88 to -0.01; 4 studies, 156 participants; low-quality evidence; small effect size).Secondary outcomesCBT versus unspecific control conditions: we found differences in favour of CBT compared with waiting-list control for self-reported depression (SMD -0.36, 95% CI -0.60 to -0.11; 5 studies, 258 participants; small effect size) and for self-reported anxiety (SMD -0.45, 95% CI -0.71 to -0.19; 4 studies, 239 participants; small effect size). We also observed differences in favour of CBT for self-reported state anger (1 study, 43 participants) and self-reported self-esteem (1 study 43 participants) compared to waiting list. We found no differences between CBT and supportive therapy (1 study, 81 participants) for self-rated depression, clinician-rated anxiety or self-rated self-esteem. Additionally, there were no differences between CBT and the waiting list for self-reported trait anger (1 study, 43 participants) or self-reported quality of life (SMD 0.21, 95% CI -0.29 to 0.71; 2 studies, 64 participants; small effect size).CBT plus pharmacotherapy versus pharmacotherapy alone: we found differences in favour of CBT plus pharmacotherapy for the Clinical Global Impression score (MD -0.75 points, 95% CI -1.21 points to -0.30 points; 2 studies, 65 participants), self-reported depression (MD -6.09 points, 95% CI -9.55 points to -2.63 points; 2 studies, 66 participants) and self-reported anxiety (SMD -0.58, 95% CI -1.08 to -0.08; 2 studies, 66 participants; moderate effect size). We also observed differences favouring CBT plus pharmacotherapy (1 study, 31 participants) for clinician-reported depression and clinician-reported anxiety.CBT versus other specific interventions: we found no differences for any of the secondary outcomes, such as self-reported depression and anxiety, and findings on self-reported quality of life varied across different studies. There is low-quality evidence that cognitive-behavioural-based treatments may be beneficial for treating adults with ADHD in the short term. Reductions in core symptoms of ADHD were fairly consistent across the different comparisons: in CBT plus pharmacotherapy versus pharmacotherapy alone and in CBT versus waiting list. There is low-quality evidence that CBT may also improve common secondary disturbances in adults with ADHD, such as depression and anxiety. However, the paucity of long-term follow-up data, the heterogeneous nature of the measured outcomes, and the limited geographical location (northern hemisphere and Australia) limit the generalisability of the results. None of the included studies reported severe adverse events, but five participants receiving different modalities of CBT described some type of adverse event, such as distress and anxiety.


Temporal and Spatial Evolution of Dengue Incidence in Brazil, 2001-2012.
In Brazil, the incidence of dengue greatly increased in the last two decades and there are several factors impeding the control of the disease. The present study focused on describing the space-time evolution of dengue in Brazil from 2001 to 2012 and analyzing the relationship of the reported cases with socio-demographic and environmental factors. The analytic units used in the preparation of thematic maps were municipalities. Statistical tests and multilevel regression models were used to evaluate the association between dengue incidence and the following factors: climate, diagnostic period, demographic density, percentage of people living in rural areas, Gross Domestic Product, Gini index, percentage of garbage collection and the rate of households with a sewage network. The largest accumulation of dengue cases in Brazil was concentrated on the Atlantic coast and in the interior part of São Paulo State. The risk of dengue in subtropical and tropical climates was 1.20-11 times lower than that observed in semi-arid climates. In 2009-2010 and 2011-2012, the risks were ten and six times higher than in 2003-2004, respectively. Dengue is a common infection in the Brazilian population, with the largest accumulation of dengue cases concentrated on the Atlantic coast and in the interior area of São Paulo State. The high dengue rates observed in the Brazilian coastal region suggest that the cases imported from neighboring countries contribute to the spread of the disease in the country. Our results suggest that several socio-demographic and environmental factors resulted in the increase of dengue in the country over time. This is likely applicable to the occurrence of other arboviruses like Zika and chikungunya. To reverse the situation, Brazil must implement effective public policies that offer basic services such as garbage collection and sanitation networks as well as reduce vector populations.


Myofascial pain: relief by post-isometric relaxation.
The post-isometric relaxation technique begins by placing the muscle in a stretched position. Then an isometric contraction is exerted against minimal resistance. Relaxation and then gentle stretch follow as the muscle releases. This technique was applied to tight, tender muscles that are commonly associated with musculoskeletal pain and was systematically tested on 351 muscle groups in 244 patients. The method produced immediate pain relief in 94%, lasting pain relief in 63%, as well as lasting relief of point tenderness in 23% of the sites treated. Patients who practiced autotherapy on a home program were more likely to realize lasting relief. Pain was relieved in both the muscle itself and at tender insertion points. The technique is useful in addition to, or in place of, local anesthetic injection or dry needling. These results confirm other observations that the increased tension of the affected muscles and the resulting pain and dysfunction are both relieved by restoring the full stretch length of the muscle.


Health Disparities: Taking on the Challenge.
The existence of significant health disparities beyond those associated with race/ethnicity, poverty, and lack of health care has drawn the attention of researchers to the "challenge of the gradient." Studies progressed from describing cross-sectional associations between disease risk and a single aspect of social disadvantage to identifying mechanisms by which these associations occur, encompassed objective and subjective measures of social status and stress processes, and used multilevel, dynamic models over the life course. The next stage is developing effective interventions targeting both the bases of disadvantage and the mediating pathways to reduce persistent disparities.


Potential of smartphone enabled otoscopy for teleconsultation and teaching.
The smartphone enabled otoscope (SEO) provides an opportunity for telemedicine and enhancing teaching of otoscopy. We describe our preliminary experience with the use of one such inexpensive device bought from an online store. It is a simple and feasible procedure which patients can perform on themselves (or guardians on their wards) after minimal training. The resolution of the image is adequate for follow up through teleconsultation. It is also a good teaching tool as it enables the sharing of views.


[Ru(bpy)2(5-cyanouracil)2]2+ as a potential light-activated dual-action therapeutic agent.
The cation cis-[Ru(bpy)(2)(5CNU)(2)](2+) (bpy = 2,2'-bipyridine; 5CNU = 5-cyanouracil) was synthesized and investigated for use as a potential light-activated dual-action therapeutic agent. The complex undergoes efficient photoinduced 5CNU ligand exchange for solvent water molecules, thus simultaneously releasing biologically active 5CNU and generating [Ru(bpy)(2)(H(2)O)(2)](2+). The latter binds covalently to ds-DNA, such that photolysis results in the generation of 3 equiv of potential therapeutic agents from a single molecule.


Highly Anisotropic Corncob as an Efficient Solar Steam-Generation Device with Heat Localization and Rapid Water Transportation.
Solar steam generation is receiving considerable interest because of its potential application in wastewater treatment and desalination. Many devices with various photothermal materials and structures have been demonstrated to be solar steam evaporators by improving their light absorption, heat loss, water transportation, and vapor escape. However, developing a biomass-based evaporator with heat localization and rapid water transportation is highly desired yet still challenging. Here, corncobs, a kind of agricultural waste with vascular bundle and "vesiculose" structures, are used to fabricate solar steam-generation devices. After high-temperature treatment, the carbonized corncobs maintain the highly anisotropic porous framework and favorable hydrophilicity and thereby have excellent thermal management and water transportation. With efficient solar absorption, heat localization, and rapid water transportation, the lightweight carbonized corncobs can float on water and generate water vapor with a high steam generation efficiency of 86.7% under 1 sun.


The natural history of hepatitis B.
Hepatitis B infection is acquired through contact with the blood of a person carrying the hepatitis B virus. The carrier rate of HBsAg varies world-wide. In many endemic areas, infection is largely acquired perinatally, while in other areas of high prevalence, transmission occurs during childhood, with intrafamilial spread being particularly important. Subclinical hepatitis B attacks are extremely frequent. The unusual clinical episode diagnosed in the adult tends to be more severe than that for virus A or non-A, non-B infection although the overall picture is similar. A fulminant course may be related to an enhanced immune response, and in such instances, HBsAg titres may be low or undetectable. About 10% of patients suffering an acute attack, more commonly males, will not clear the virus and will become chronic carriers. These may remain 'healthy' or suffer from various grades of chronic hepatitis and cirrhosis. Chronicity is related to impairment of humoral and cell-mediated immunity. There are two phases of hepatitis B infection, the replicative and the integrated, the former being recognized by the presence of hepatitis B viral DNA in serum. Relapses of chronic hepatitis B may be related to conversion from replicative to integrated stages, to spontaneous reactivation, or to super-added virus infection, especially with delta virus.


Topical minoxidil therapy for androgenetic alopecia. A 30-month study.
Seventy-two adult male patients were entered into a double-blind, placebo-controlled investigation using 2% to 3% topical minoxidil solution for androgenetic alopecia. Fifty-nine patients completed the initial 12 months, and continued to use 3% topical minoxidil solution in an open study design. Hair regrowth (as measured by hair counts and bald-area diameters) was noted in all treatment groups at four months, and appeared to peak at approximately 12 months. At 30 months, mean hair counts had decreased from the 12-months level, but remained elevated over baseline counts, while mean bald-area diameters returned to baseline. However, 70% of the patients who did continue to use the drug for 30 months had 50% or more hairs than when they originally started the drug therapy. A subset of patients appeared to sustain a continued increase in hair counts after 12 months. No systemic side effects were noted.


Sudden Infant Death Syndrome and Safe Sleep on Twitter: Analysis of Influences and Themes to Guide Health Promotion Efforts.
In the United States, sudden infant death syndrome (SIDS) is the leading cause of death in infants aged 1 month to 1 year. Approximately 3500 infants die from SIDS and sleep-related reasons on a yearly basis. Unintentional sleep-related deaths and bed sharing, a known risk factor for SIDS, are on the rise. Furthermore, ethnic disparities exist among those most affected by SIDS. Despite public health campaigns, infant mortality persists. Given the popularity of social media, understanding social media conversations around SIDS and safe sleep may assist the medical and public health communities with information needed to spread, reinforce, or counteract false information regarding SIDS and safe sleep. The objective of our study was to investigate the social media conversation around SIDS and safe sleep to understand the possible influences and guide health promotion efforts and public health research as well as enable health professionals to engage in directed communication regarding this topic. We used textual analytics to identify topics and extract meanings contained in unstructured textual data. Twitter messages were captured during September, October, and November in 2017. Tweets and retweets were collected using NUVI software in conjunction with Twitter's search API using the keywords: "sids," "infant death syndrome," "sudden infant death syndrome," and "safe sleep." This returned a total of 41,358 messages, which were analyzed using text mining and social media monitoring software. Multiple themes were identified, including recommendations for safe sleep to prevent SIDS, safe sleep devices, the potential causes of SIDS, and how breastfeeding reduces SIDS. Compared with September and November, more personal and specific stories of infant loss were demonstrated in October (Pregnancy and Infant Loss Awareness Month). The top influencers were news organizations, universities, and health-related organizations. We identified valuable topics discussed and shared on Twitter regarding SIDS and safe sleep. The study results highlight the contradicting information a subset of the population is exposed to regarding SIDS and the continued controversy over vaccines. In addition, this analysis emphasizes the lack of public health organizations' presence on Twitter compared with the influence of universities and news media organizations. The results also demonstrate the prevalence of safe sleep products that are embedded in safe sleep messaging. These findings can assist providers in speaking about relevant topics when engaging in conversations about the prevention of SIDS and the promotion of safe sleep. Furthermore, public health agencies and advocates should utilize social media and Twitter to better communicate accurate health information as well as continue to combat the spread of false information.


Comparative genomic hybridization studies in hydatidiform moles and choriocarcinoma: amplification of 7q21-q31 and loss of 8p12-p21 in choriocarcinoma.
Comparative genomic hybridization (CGH) was utilized to investigate genetic changes from archived cases of choriocarcinoma (n = 12) and hydatidiform moles (n = 7). Test DNA was extracted from paraffin-embedded tissues, amplified using total universal PCR, and co-hybridized with control DNA to normal metaphases. Comparative genomic hybridization findings showed chromosomal imbalances in 9 of 12 cases of choriocarcinoma. By contrast, all hydatidiform moles showed normal CGH profiles. Consistent findings in choriocarcinoma included deletion at 8p (5 cases) and amplification at 7q (4 cases). A tumor suppressor gene (e.g., N33) at 8p and/or a growth regulator at 7q could play a role in the initiation of choriocarcinoma and its progression. This is the first study showing specific alterations in choriocarcinomas by CGH, and illustrates the utility of this technique in elucidating genetic changes in gynecological tumors.


A study of the dopamine D2 receptor gene in pathological gambling.
Pathological gambling has been termed both the 'pure' and the 'hidden' addiction. 'Pure' because it is not associated with the intake of any addicting substance, and 'hidden' because it is an extension of a common, socially accepted behaviour. The Taq A1 variant of the human DRD2 gene has been associated with drug addiction, some forms of severe alcoholism, and other impulsive, addictive behaviours. We have sought to determine if there is a similar association with pathological gambling. A total of 222 non-Hispanic Caucasian pathological gamblers from multiple sites across the US participated in the study. Of these 171 donated a sample of blood, 127 filled out several questionnaires, and 102 did both. Of the 171 pathological gamblers 50.9% carried the D2A1 allele versus 25.9% of the 714 known non-Hispanic Caucasian controls screened to exclude drug and alcohol abuse, p < 0.00000001, odds ratio (OR) = 2.96. For the 102 gamblers who filled out the questionnaires, 63.8% of those in the upper half of the Pathological Gambling Score (more severe) carried the D2A1 allele (OR versus controls = 5.03), compared to 40.9% in the lower half (less severe). Of those who had no comorbid substance abuse, 44.1% carried the D2A1 allele, compared to 60.5% of those who had comorbid substance abuse. Forty-eight controls and 102 gamblers completed a shorter version of the Pathological Gambling Score. Of the 45 controls with a score of zero, 17.8% carried the D2A1 allele. Of the 99 gamblers with a score of 5 or more, 52.5% carried the D2A1 allele (chi 2 = 15.36, p = 0.00009). These results suggest that genetic variants at the DRD2 gene play a role in pathological gambling, and support the concept that variants of this gene are a risk factor for impulsive and addictive behaviours.


Predator faunas past and present: quantifying the influence of waterborne cues in divergent ecotypes of the isopod Asellus aquaticus.
Waterborne chemical cues are an important source of information for many aquatic organisms, in particular when assessing the current risk of predation. The ability to use chemical cues to detect and respond to potential predators before an actual encounter can improve prey chances of survival. We investigated predator recognition and the impact of chemical cues on predator avoidance in the freshwater isopod Asellus aquaticus. This isopod has recently colonised a novel habitat and diverged into two distinct ecotypes, which encounter different predator communities. Using laboratory-based choice experiments, we have quantified behavioural responses to chemical cues from predators typical of the two predator communities (larval dragonflies in the ancestral habitat, perch in the newly colonised habitat) in wild-caught and lab-reared Asellus of the two ecotypes. Individuals with prior experience of predators showed strong predator avoidance to cues from both predator types. Both ecotypes showed similar antipredator responses, but sexes differed in terms of threat-sensitive responses with males avoiding areas containing predator cues to a larger extent than females. Overall, chemical cues from fish elicited stronger predator avoidance than cues from larval dragonflies. Our results indicate that in these isopods, prior exposure to predators is needed to develop antipredator behaviour based on waterborne cues. Furthermore, the results emphasise the need to analyse predator avoidance in relation to waterborne cues in a sex-specific context, because of potential differences between males and females in terms of vulnerability and life history strategies.


[The clinical efficacy of hepatic artery infusion chemotherapy and chemoembolization in the treatment of liver metastases].
The efficacy and clinical experience of transcatheter hepatic artery infusion chemotherapy alone or chemoembolization in 118 patients with hepatic metastases were reviewed. Hepatic arterial infusion chemotherapy followed by embolization with lipiodol suspension and gelatin sponge pieces was carried out in 72 cases, infusion chemotherapy followed by embolization with lipiodol suspension in 32, and arterial infusion chemotherapy alone in 14. The results showed that the clinical efficacy of the first method was the best while that of the third method was the worst. The best effect was seen in patients with the single and hypervascular metastatic focus. The overall survival rate was 86.0%, 25.0%, 3.0% in 1 year, 3 years and 5 years, respectively.


Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism-Review.
Glutathione (GSH) was initially identified and characterized for its redox properties and later for its contributions to detoxification reactions. Over the past decade, however, the essential contributions of glutathione to cellular iron metabolism have come more and more into focus. GSH is indispensable in mitochondrial iron-sulfur (FeS) cluster biosynthesis, primarily by co-ligating FeS clusters as a cofactor of the CGFS-type (class II) glutaredoxins (Grxs). GSH is required for the export of the yet to be defined FeS precursor from the mitochondria to the cytosol. In the cytosol, it is an essential cofactor, again of the multi-domain CGFS-type Grxs, master players in cellular iron and FeS trafficking. In this review, we summarize the recent advances and progress in this field. The most urgent open questions are discussed, such as the role of GSH in the export of FeS precursors from mitochondria, the physiological roles of the CGFS-type Grx interactions with BolA-like proteins and the cluster transfer between Grxs and recipient proteins.


Tonal targets in early child English, Spanish, and Catalan.
This study analyses the scaling and alignment of low and high intonational targets in the speech of 27 children - nine English-speaking, nine Catalan-speaking and nine Spanish-speaking - between the ages of two and six years. We compared the intonational patterns of words controlled for number of syllables and stress position in the child speech to the adult target speech provided by their mothers, and to a dataset of adult-directed speech recorded at a later stage for the purpose of measuring pitch height. A corpus of 624 utterances was elicited using a controlled naming task and analysed within the Autosegmental Metrical framework. Measuring the pitch height and pitch timing of nuclear pitch accents, we found that once the effects of syllable duration are accounted for, young children reach tonal targets with remarkable precision. Overall, the results indicate that the phonetic aspects of intonation are acquired from a very early age. Even the youngest children show adult-like alignment of the low target, although mastery of the high target increases with age. Young Spanish-speaking children, however, show a more precise attainment of pitch scaling and alignment of their (high) tonal targets than do Catalan and English children; where the ambient language lies within a general prosodic typology appears to influence the acquisition of tonal targets.


[Testicular cancer metastatic to multiple organs including the stomach, kidneys, and skin: a case report].
A 39-year-old man whose chief complaints were general fatigue and bloody phlegm was diagnosed with testicular cancer and underwent left high orchiectomy at an affiliated hospital. The histopathologic diagnosis was chorio carcinoma. Several imaging examinations revealed the metastases in the lung, liver, brain, stomach, kidneys and skin. In spite of various chemotherapies, he died 17 months after the operation. Skin metastasis of testicular cancer is very rare and this is the twelfth case reported in the world, to our knowledge. The significance of skin metastasis in testicular cancer is discussed.


Unfolding and conformational distributions during protein precipitation.
The association of misfolded proteins, or aggregation, is a critical problem in a number of human diseases as well during the expression, refolding, formulation, and delivery of therapeutic proteins. In this study, we investigate lysozyme precipitation with hydrogen exhange using nuclear magnetic resonance (NMR) and mass spectrometry (MS). We show that MS can reveal the presence of conformational distributions, albeit without the detailed structural information afforded by NMR. Further, we find that increases in precipitant concentration alter the structure and composition of precipitates. The selective unfolding of one portion of the protein in these precipitates is correlated with hydrogen exchange patterns observed under nonprecipitating conditions and in other studies of lysozyme.


Eruptive Seborrheic Keratoses Are Associated With a Co-Occurring Malignancy in the Majority of Reported Cases: A Systematic Review.
Eruptive seborrheic keratoses (ESK) is a benign skin condition that has been associated with malignant and nonmalignant diseases. We conducted a systematic review of reported cases of ESK to identify and summarize associated comorbidities. MEDLINE and Embase were searched from database inception (1946) to July 31, 2020 for original articles describing ESK with or without a co-occurring condition. Subject demographics, as well as details of ESK and associated diagnoses were extracted from 76 articles (70 case reports, 3 case series, 3 case control studies) representing 92 patients. In total, 76.1% (n = 70/92) of patients with ESK had a co-occurring malignancy, 4.3% (n = 4/92) presented with a nonmalignant condition, 9.8% (n = 9/92) experienced ESK as an adverse drug reaction, and 9.8% (n = 9/92) did not report any underlying medical condition. ESK preceded a cancer diagnosis in 76.1% (n = 70/92) of patients with a mean latency period of 4.0 months (range: 0.25-9 months). The most common malignancies associated with ESK were cutaneous T-cell lymphoma (n = 10/70, 14.3%) and gastrointestinal adenocarcinoma (n = 9/70, 12.9%). ESK preceded nonmalignant conditions or no disease in 14.1% (n = 13/92) of patients with a mean latency period of 3.1 months (range: 0.75-6 months). Drug-induced ESK occurred in 9.8% (n = 9/92) of patients with a mean latency period of 7.1 weeks after changing medication. Although the role of ESK as a paraneoplastic cutaneous marker is debated, healthcare providers should consider screening for underlying malignancy in patients presenting with ESK. Larger studies are needed to confirm its role as a marker for disease.


SB-258741: a 5-HT7 receptor antagonist of potential clinical interest.
Recently, a series of 5-HT7 receptor antagonists have been developed (24,29,36,68). Among them SB-258741, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine, (compound "13" in 36,37) was one of the most potent and specific compounds. Due to a lack of specific ligands the pharmacology of 5-HT7 receptor antagonists is still relatively unexplored. It has been suggested, however, that 5-HT7 receptor ligands could be useful in the therapy of various disorders such as sleep disorders, schizophrenia, depression, migraine, epilepsy, pain, or memory impairment. Many of these conceivable indications are not supported by pharmacological data. It is, therefore, of particular interest to review the data generated from studies of one of these most potent and specific 5-HT7 receptor antagonists, SB-258741, with a goal of testing the validity of the proposed clinical indications. In this review, the author describes pharmacology of this compound in order to define its potential clinical use. The available safety pharmacology data are discussed in an attempt to predict potential side effects of specific 5-HT7 receptor antagonists.


Light-Interacting iron-based nanomaterials for localized cancer detection and treatment.
To improve the prognosis of cancer patients, methods of local cancer detection and treatment could be implemented. For that, iron-based nanomaterials (IBN) are particularly well-suited due to their biocompatibility and the various ways in which they can specifically target a tumor, i.e. through passive, active or magnetic targeting. Furthermore, when it is needed, IBN can be associated with well-known fluorescent compounds, such as dyes, clinically approved ICG, fluorescent proteins, or quantum dots. They may also be excited and detected using well-established optical methods, relying on scattering or fluorescent mechanisms, depending on whether IBN are associated with a fluorescent compound or not. Systems combining IBN with optical methods are diverse, thus enabling tumor detection in various ways. In addition, these systems provide a wealth of information, which is inaccessible with more standard diagnostic tools, such as single tumor cell detection, in particular by combining IBN with near-field scanning optical microscopy, dark-field microscopy, confocal microscopy or super-resolution microscopy, or the highlighting of certain dynamic phenomena such as the diffusion of a fluorescent compound in an organism, e.g. using fluorescence lifetime imaging, fluorescence resonance energy transfer, fluorescence anisotropy, or fluorescence tomography. Furthermore, they can in some cases be complemented by a therapeutic approach to destroy tumors, e.g. when the fluorescent compound is a drug, or when a technique such as photo-thermal or photodynamic therapy is employed. This review brings forward the idea that iron-based nanomaterials may be associated with various optical techniques to form a commercially available toolbox, which can serve to locally detect or treat cancer with a better efficacy than more standard medical approaches. STATEMENT OF SIGNIFICANCE: New tools should be developed to improve cancer treatment outcome. For that, two closely-related aspects deserve to be considered, i.e. early tumor detection and local tumor treatment. Here, I present various types of iron-based nanomaterials, which can achieve this double objective when they interact with a beam of light under specific and accurately chosen conditions. Indeed, these materials are biocompatible and can be used/combined with most standard microscopic/optical methods. Thus, these systems enable on the one hand tumor cell detection with a high sensitivity, i.e. down to single tumor cell level, and on the other hand tumor destruction through various mechanisms in a controlled and localized manner by deciding whether or not to apply a beam of light and by having these nanomaterials specifically target tumor cells.


Role of peroxisome proliferator-activated receptor gamma coactivator 1alpha in AKT/PKB-mediated inhibition of hepatitis B virus biosynthesis.
Hepatitis B virus (HBV) transcription and replication are essentially restricted to hepatocytes because liver-enriched transcription factors govern viral RNA synthesis. The level of transcription from the HBV promoters depends on both the transcription factors binding to these regulatory sequence elements and their ability to recruit coactivators capable of mediating assembly of the transcription preinitiation complex containing RNA polymerase II. Nuclear receptors are a primary determinant of HBV pregenomic RNA synthesis and, hence, viral replication. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) enhances the activity of nuclear receptors and, consequently, HBV biosynthesis. PGC1α is also an important target of signal transduction pathways involved in hepatic glucose and lipid homeostasis, suggesting that this coactivator may have an important role in modulating HBV biosynthesis under various physiological conditions. Consistent with this suggestion, v-akt murine thymoma viral oncogene homolog/protein kinase B (AKT/PKB) is shown to modulate PGC1α activity and, hence, HBV transcription and replication in a cell line-specific manner. In addition, AKT can modulate HBV replication in some but not all cell lines at a posttranscriptional step in the viral life cycle. These observations demonstrate that growth and nutritional signals have the capacity to influence viral production, but the magnitude of these effects will depend on the precise cellular context in which they occur.


Return to duty after type III open tibia fracture.
Despite the high incidence of battlefield orthopaedic injuries, long-term outcomes and return to duty (RTD) status have rarely been studied. Our purpose was to determine the RTD rate for soldiers who sustained Type III open tibia fractures in active combat. One hundred fifteen soldiers who sustained battle-related Type III open tibia fractures were retrospectively reviewed. The Army Physical Evaluation Board database was reviewed to determine which soldiers were able to RTD and the disability ratings of those not able to RTD. The overall RTD rate was 18%, isolated open fractures had a RTD rate of 22%, salvaged extremities had a RTD rate of 20.5%, and amputees had a RTD rate of 12.5%. Older age and higher rank were both significant factors in increasing the likelihood of RTD and amputees had significantly higher disability ratings than those with salvaged extremities. Despite the severe nature of combat extremity wounds, 20% of patients with salvaged Type III open tibia fractures and 22% with isolated injuries were able to return to active duty. These rates are similar to those reported for civilian amputees. Amputees in our cohort were less likely to RTD.


Differential expression of neuroD in primary cultures of cerebral cortical neurons.
We have investigated the expression patterns of a basic helix-loop-helix regulatory gene, neuroD, in primary cultures of murine cerebral cortical neurons. The differentiation states of neurons in primary cultures were determined by the sensitivity of neurons to glutamate toxicity and the expression of specific proteins such as the phosphorylated form of a 200-kDa neurofilament, HPC-1/syntaxin 1A, and cell adhesion molecule L1. The expression of neuroD was determined by RT-PCR analysis and in situ hybridization. The experimental results thus obtained revealed that neuronal maturation is initiated between Day 7 and Day 11 in the culture as already known, and that the expression of neuroD decreases with increasing days in culture. Based on these findings, it was concluded that neuroD is expressed in immature neurons but not in mature ones.


Lipid Membrane Binding and Cell Protection Efficacy of Poly(1,2-butylene oxide)-b-poly(ethylene oxide) Copolymers.
Poloxamers consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) segments can protect cell membranes against various forms of stress. We investigated the role of the hydrophobic block chemistry on polymer/membrane binding and cell membrane protection by comparing a series of poly(butylene oxide)-b-PEO (PBO-b-PEO) copolymers to poloxamer analogues, using a combination of pulsed-field-gradient (PFG) NMR experiments and a lactate dehydrogenase (LDH) cell assay. We found that the more hydrophobic PBO-b-PEO copolymers bound more significantly to model liposomes composed of 1-palmitol-2-oleoyl-glycero-3-phosphocholine (POPC) compared to poly(propylene oxide) (PPO)/PEO copolymers. However, both classes of polymers performed similarly when compared by an LDH assay. These results present an important comparison between polymers with similar structures but with different binding affinities. They also provide mechanistic insight as enhanced polymer/lipid membrane binding did not directly translate to increased cell protection in the LDH assay, and therefore, additional factors need to be considered when trying to achieve greater membrane protection efficacy.


[Quinidine-induced lichenoid photodermatitis].
Quinidine-induced lichenoid photodermatitis was definitely isolated by Berger and Sesody in 1982. We had an opportunity to observe 4 cases of this striking clinical condition and encountered some particularities. Our patients (2 men and 2 women) were 60, 64, 81 and 68 years old respectively. All had a previous cardiovascular history; diabetes was also present in patient No. 2, and hypertension in patient No. 4. All patients were taking other drugs. The first patient presented with a 4-year old lichenoid eruption on the hands, associated with some degree of follicular keratosis. The second and third patients had a mixture of mainly lichenoid lesions on sun-exposed areas, but eczematous and desquamative lesions were also encountered. The fourth patient had typical lichenoid photodermatitis with occasional bullae on the arms and legs. In all patients the disease appeared or worsened in the Summer. It disappeared rapidly in 3 cases upon withdrawal of quinidine (patients No. 1 and 2) or hydroquinidine (patient No. 3), but it lasted longer in patient No. 4, with pigmented sequelae. Histological examination of the skin was consistent with a lichenoid eruption in all cases. However, an immunopathological study revealed a pemphigoid-like pattern in patients No. 1 and 2, and ovoid bodies more suggestive of lichen planus in patient No. 4. Photobiology was not performed. A review of the literature showed that the terms "lichen planus", "lichenoid", "lichenification" or "violaceus hue" were frequently encountered, and we suggest quinidine as one of the most common agents of lichenoid reaction.(ABSTRACT TRUNCATED AT 250 WORDS)


Control of cancer pain by epidural infusion of morphine.
Pain that cannot be controlled by traditional oral and parenteral methods in those patients with advanced cancer can be alleviated by spinal administration of narcotics. Epidural and intrathecal infusion with morphine causes analgesia by blocking spinal receptors without significant long-term central nervous, gastrointestinal, and genitourinary system effects. Of the total of 33 patients, epidural catheters inserted in 20 patients then connected by a subcutaneous tunnel to a continuous infusion system. Implanted pumps were used in each of these patients. Because of the cost and limitations of the implanted pumps, epidural catheters were connected, either directly or by subcutaneous reservoirs, to external ambulatory infusion pumps in the remaining 13 patients. Patient assessment by a linear analogue scale to measure pain levels determined that 23 of the 33 total patients (70%) had excellent or good relief of pain. The delivery of spinal administration of narcotics to treat intractable cancer pain in patients is safe. Most importantly, this method of delivery can be used in community hospitals, in outpatient settings, and in home health care programs.


Application of computer-assisted dynamic navigation in complex root canal treatments: Report of two cases of calcified canals.
Root canal treatment and non-vital bleaching of teeth with pulp canal obliteration may represent a complex challenge to the clinician. This report describes the usefulness of the computer-assisted dynamic navigation system for the root canal treatment of two cases of teeth with a history of traumatic injury, extensively obliterated root canals and crown discoloration. Clinical and cone-beam computed tomographic evaluations were completed prior to procedures and 12 months after treatment. Both cases were treated using a computer-assisted dynamic navigation system coupled to a high-speed handpiece in order to establish the location and orientation of the partially obliterated canal and endodontic access route planning. The system allowed an accurate localisation of the root canal with a conservative access cavity. At the 12-month recall examination, the patients continue to be symptom-free, with a normal appearance of the mucogingival complex, adequate restoration of the tooth colour and intact periapical structures.


Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing's Syndrome.
Endogenous Cushing's syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed "Cushing's disease") and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.


The ratio of thioredoxin/Keap1 protein level is a predictor of distant metastasis in colorectal cancer.
Thioredoxin can reduce the cysteine group of Keap1 which could induce proteasome degradation of Nrf2, PGAM5 and Bcl-xL. Nrf2 regulates redox balance and Bcl-xL is anti-apoptotic and both are important in tumor progression. The protein levels of Keap1, thioredoxin, PGAM5 and Bcl-xL in the normal and tumor tissues of 64 subjects with colorectal cancer (CRC) were determined by western blot. The tumor had higher Keap1 but lower PGAM5s and Bcl-xL protein expression than the normal tissue. The ratio of thioredoxin/Keap1 protein level in the normal (OR: 0.12; 95% CI: 0.02-0.83) or tumor tissue (OR: 0.17; 95% CI: 0.03-0.89) was a negative predictor for distant metastasis in CRC. Keap1-mediated degradation of PGAM5 and Bcl-xL may be active in CRC. The ratio of thioredoxin/Keap1 protein level may be useful for suggesting distant metastasis in CRC.


Real-Time PCR Detection of Dogwood Anthracnose Fungus in Historical Herbarium Specimens from Asia.
Cornus species (dogwoods) are popular ornamental trees and important understory plants in natural forests of northern hemisphere. Dogwood anthracnose, one of the major diseases affecting the native North American Cornus species, such as C. florida, is caused by the fungal pathogen Discula destructiva. The origin of this fungus is not known, but it is hypothesized that it was imported to North America with its host plants from Asia. In this study, a TaqMan real-time PCR assay was used to detect D. destructiva in dried herbarium and fresh Cornus samples. Several herbarium specimens from Japan and China were detected positive for D. destructiva, some of which were collected before the first report of the dogwood anthracnose in North America. Our findings further support that D. destructiva was introduced to North America from Asia where the fungus likely does not cause severe disease.


Reciprocal modulation of eye-blink and pinna-flexion components of startle during reward anticipation.
Because expectancies play a central role in current theories of dopaminergic neuron function, it is important to develop measures of reward anticipation processes. In the present study, reflexogenic bursts of white noise were presented to 39 healthy young adults as they awaited rewards and punishments in a gambling-like task. The rewards were small pieces of chocolate; the punishments, segments of bitter-tasting banana peel. Consistent with prior research on affective valence, postauricular reflexes were larger prior to rewards than punishments, whereas the reverse was true for acoustic blink reflexes. We theorized that potentiation of the postauricular reflex prior to consuming appetizing food is related to the priming of ear-retraction musculature during nursing in our remote ancestors.


Expression of MicroRNA-155 is Downregulated in Peripheral Blood Mononuclear Cells of Chronic Hepatitis B Patients.
Persistent hepatitis B virus (HBV) infection is sustained by inadequate immune responses, either natural or acquired. Recent studies have suggested that immune responses to viral infection may be affected by microRNA (miR)-155, via its involvement in immune cell differentiation and maturation. However, little is known on the specific interaction between miR-155 and HBV in host antiviral immunity. This study evaluated the levels of miR-155 in peripheral blood mononuclear cells (PBMCs) of chronic hepatitis B (CHB) patients, relative to that of healthy subjects, and investigated an association between miR-155 levels and HBV DNA or alanine aminotransferase (ALT). Total RNA was extracted from peripheral venous blood samples of 90 treatment-naive patients with chronic HBV infection and 20 healthy volunteers. The levels of miR-155 in the PBMCs were measured by real-time quantitative polymerase chain reaction. Serum HBV DNA and liver enzymes were estimated using standard clinical laboratory methods. In the HBV-infected patients, the miR-155 levels were significantly lower than in the healthy controls (P = 0.001). Chronic HBV-infected patients with elevated ALT had higher levels of miR-155 compared with patients with normal ALT (P = 0.014). No correlations were found between miR-155 and ALT or HBV DNA. The miR-155 appeared to be suppressed during HBV infection. The significantly higher miR-155 levels in ALT-elevated patients infected with HBV suggest that miR-155 levels in PBMCs correlate with the immune state of patients with chronic HBV infection.


Urinary sulfated bile acids: a new simple urine test for cholestasis in infants and children.
Measurement of urinary sulfated bile acid (USBA) has been reported as a simple urine test that reflects the degree of cholestasis. The authors report the diagnostic value of this new laboratory test in various cholestatic conditions affecting infants and children. A urine sample was collected from 4 surgical neonates with parenteral nutrition-induced cholestasis and 48 patients with biliary atresia (BA). USBA was measured by direct enzymatic assay. In 3 patients receiving parenteral nutrition, USBA increased with caloric gains. For one surgical patient, a decrease in calories because of liver dysfunction resulted in a decrease of USBA, closely reflecting the fluctuations of caloric intake. In patients with BA, a significant positive correlation was noted between serum bile acid and USBA (r = 0.85; P <.01). Ten of 14 febrile episodes in 6 patients with liver dysfunction and increased C-reactive protein showed elevated USBA, thus diagnosed as cholangitis. Four febrile episodes caused by viral infection showed no elevation of USBA. USBA is a simple and sensitive noninvasive test reflecting the degree of cholestasis in infants and children. USBA correlated highly with serum bile acid levels and may be helpful in diagnosis of cholestasis caused by cholangitis without blood sampling.


Cut-off values of 6-min walk test and sit-to-stand test for determining symptom burden in atrial fibrillation.
Since symptomatology is a major predictor of quality of life and an endpoint for the management of atrial fibrillation (AF), practical approaches for objectively interpreting symptom burden and functional impairment are needed. We aimed to provide cut-off values for two frequently used field tests to be able to objectively interpret symptom burden in atrial fibrillation. One hundred twenty-five patients with AF were evaluated with European Heart Rhythm Association (EHRA) score, 6-min walk test (6MWT), 30 s sit-to-stand test (30 s-STST), Short-Form 36 (SF-36), International Physical Activity Questionnaire-Short Form (IPAQ-SF), and spirometry. Patients with EHRA 1 were classified as "asymptomatic", and those with EHRA 2-4 as "symptomatic". Cut-off values of 6MWT and 30 s-STST for discriminating between these patients were calculated. The optimal cut-off value was "450 m" for 6MWT (sensitivity: 0.71; specificity of 0.79) and "11 repetitions" for 30 s-STST (sensitivity 0.77; specificity of 0.70). Area under ROC curve was 0.75 for both tests (p < 0.001). Discriminative properties of the two tests were similar, and they were significantly correlated (r = 0.58; p < 0.001). Subgroup analysis revealed patients below cut-off values also had worse outcomes in SF-36, IPAQ-SF, and spirometry. In patients with AF, walking < 450 m in 6MWT or performing < 11 repetitions in 30 s-STST indicates increased symptom burden, as well as impaired exercise capacity, quality of life, physical activity participation, and pulmonary function. These cut-off values may help identifying patients who may require adjustments in their routine treatment or who may benefit from additional rehabilitative approaches.